Novel substituted alkane compounds and uses thereof

ABSTRACT

The present invention includes compounds, methods of making the compounds, compositions including the compounds and/or use of the compounds and compositions, wherein the compounds of the following formulas

BACKGROUND OF THE INVENTION

There are many known uses for antimicrobial agents as antiseptics andfor cleaning, disinfecting and sterilizing, and for preventing andtreating many diseases. Because microorganisms are often able to developresistant strains to antimicrobial agents, there is a continual need forthe development of new antimicrobial compounds and compositionsemploying such compounds. Such compositions are known in the art and areused, for example, in the health care industry, food service industry,meat processing industry, in the workplace and in the home.

Bacteria, fungi, protozoa, viruses, algae and other microorganisms arealways present in the environment and may be undesirable because theycause illness or death of humans and animals, create odors and damage ordestroy a wide variety of materials. The species and numbers ofmicroorganisms present vary depending on the characteristics of theparticular environment, i.e., the nutrients, moisture and temperature.For example, surfaces including walls, floors, food preparationsurfaces, instruments and devices may become contaminated by fungal,protozoan, algal, bacterial or viral microorganisms. Furthermore, manyorganic, synthetic and natural materials such as plastic coatings andobjects, wood, paper and natural fibers serve as nutrients formicroorganisms and may be degraded by the microorganisms. Additionallycertain microorganisms are capable of remaining viable in a dormantstate on floors or on objects for long periods of time until they aredeposited in a proper environment for growth. As a result,microorganisms can be spread by walking on floors, brushing againstwalls or furniture or by handling objects (e.g., towels, instruments).

Under the appropriate conditions, microbes have a tendency to adhere tosurfaces and initiate the formation of a biofilm. A biofilm is acommunity of microbes adhering to an inert or living surface. Microbesgrowing in biofilms are more resistant to antibiotics and disinfectantsthan planktonic cells and the resistance increases with the age of thebiofilm. Biofilms can form on virtually any surface including contactlenses, ship hulls, pipelines, rocks, biomedical devices and implants,and mucous surfaces (Dunne, Clinical Microbiological Reviews, 15, 155,2002). Biofilms cause a variety of problems, including, but not limitedto, increased frictional resistance to fluids in water conduits,decreased heat transfer from heat exchanges, pneumoniae, otitis media,dental plaque, and contamination of medical devices such as endoscopes,catheters, prosthetic devices and medical implants.

Several different classes of agents have been used in antimicrobialcompositions, including, bisguanidine, diphenyl compounds, benzylalcohols, trihalocarbanilides, quaternary ammonium compounds,exthoxlated phenols and phenolic compounds such as halo-substitutedphenolic compounds like p-chloro-m-xylenol and triclosan (U.S. Pat. No.6,136,771). Phenolics such as triclosan are a class of antimicrobialagents which have been demonstrated to have broad spectrum activityagainst a variety of microorganisms (WO 99/51094 and Domagala et al. in“Resolving the Antibiotic Paradox”, ed. by Rosen and Mabashery, page269, 1998). While Domagala et al. teach some diphenolic methanederivatives as having in vitro anti-bacterial activity, Domagala et al.teaches that these compounds do not have in vivo anti-bacterial activitywhen administered orally or subcutaneously. This is in sharp contrast tocompounds of the present invention which surprisingly, do have in vivoanti-bacterial activity and other antimicrobial activity whenadministered topically or subcutaneously.

The increasing prevalence of bacteria and other microbes that areresistance to existing antimicrobial agents necessitates theidentification of new classes of antimicrobials. Accordingly there is aneed both in industry and in the home for safe and effectiveantimicrobial compositions which can be used as antimicrobials in or ona wide variety of substances and surfaces to reduce or eliminatemicroorganisms and which can be used to therapeutically orprophylactically treat animals, plants or inanimate objects.

None of the prior teachings, described above or elsewhere, disclose thenovel compounds of the present invention or the successful use of acompound of Formulas I, II and/or III (henceforth “Formulas I-III”) asan antimicrobial agent. It is therefore an object of this invention toprovide compounds of Formulas I-III that are useful as agents for thetreatment of bacterial, viral, protozoan, or fungal infections both invivo (including but not limited to parenterally and topically) and forinhibiting bacterial, viral, protozoan, algal or fungal growth, forexample on surfaces, in biofilms, or in liquids.

SUMMARY OF THE INVENTION

The present invention includes antimicrobial compositions and/or use ofthe compositions comprising one or more compounds of the invention andmethods of making the compounds, having one of the following FormulasI-III:

Wherein

-   “a” may be absent or is a single C—C bond    -   X¹ and X² may be at any position on benzene ring and are        independently hydrogen, a C1-C20 alkyl group or a C₂-C₂₀ alkenyl        group which may be branched or unbranched or a C3-C20        hydrocarbon group which may be substituted or unsubstituted        cycloalkyl group, chloro, bromo, fluoro, methoxy, ethoxy,        dimethylamino, dimethylaminomethyl;-   Y¹ and Y² may be at any position on benzene ring and are    independently hydrogen, chloro, bromo, fluoro, cyano and nitro    group;-   R¹ and R² are independently hydrogen, a C1-C20 alkyl group which may    be branched or unbranched or a C3-C20 hydrocarbon group which may be    substituted or unsubstituted cycloalkyl group. Alternatively, R1 and    R2 are such that together they may form a C5-C20 substituted or    unsubstituted hydrocarbon ring;-   R⁷ and R^(7′) are independently one of the following: hydrogen or    -   wherein R⁹ is H, substituted or unsubstituted straight chain,        branched or cyclic alkyl, alkenyl or alkynyl, —Ar or        —(CH₂)_(n)Ar, —(C₂)_(m)C(═O)R¹¹, —(C₂)_(n)CN, heterocyclyl,        heteroaryl, —(C₂)_(n)heterocycyl, —(CH₂)_(n)-heteroaryl,    -   m=1, 2, 3, 4, 5, 6    -   n=1, 2, 3, 4, 5, 6,    -   R¹¹ is H, a substituted or unsubstituted straight chain,        branched or cyclic lower alkyl, lower alkenyl or lower alkynyl,        or an —Ar or —(CH₂)_(n)Ar;-   R⁸ is independently hydrogen, a cephalosporin moiety including but    not limited to one of the following:-   Where R¹⁰ includes but is not limited to benzylsulfanylmethyl,    phenoxyymethyl, hydroxy-phenylmethyl, (thiophen-2-yl)methyl,    (2-amino-thiazol-4-yl)-methoxyimino-methyl group-   or R⁸ is a penem moiety including but not limited to one of the    following:-   and wherein the hydroxy group, OR⁸, R⁷ and R^(7′) may be at any    position on the benzene ring.    or Formula II    wherein-   X¹ and X² may be at any position on benzene ring and are    independently hydrogen, a C1-C20 alkyl group or a C₂-C₂₀ alkenyl    group which may be branched or unbranched or a C3-C20 hydrocarbon    group which may be substituted or unsubstituted cycloalkyl group,    chloro, bromo, fluoro, methoxy, ethoxy, dimethylamino,    dimethylaminomethyl;-   Y¹ and Y² may be at any position on benzene ring and are    independently hydrogen, chloro, bromo, fluoro, cyano and nitro    group;-   R³, R^(3′) and R⁴ are independently hydrogen, chloro, bromo, fluoro,    cyano, trifluoromethyl, a C1-C20 alkyl group which may be branched    or unbranched or a C3-C20 hydrocarbon group which may be substituted    or unsubstituted cycloalkyl group. Alternatively, R³ and R⁴ are such    that together they may form a C4-C15 substituted or unsubstituted    hydrocarbon ring. Alternatively, R^(3′) and R³ are such that    together they may form a C3-C15 substituted or unsubstituted    hydrocarbon ring.-   R⁷ and R^(7′) are independently one of the following: hydrogen or    wherein    -   R⁹ is H, substituted or unsubstituted straight chain, branched        or cyclic alkyl, alkenyl or alkynyl, —Ar or —(C₂)_(n)Ar,        —(C₂)_(m)C(═O)R¹¹, —(C₂)_(n)CN, heterocyclyl, heteroaryl,        —(CH₂)_(n-)heterocycyl, —(CH₂)_(n)-heteroaryl,    -   m=1, 2, 3, 4, 5, 6;    -   n=1, 2, 3, 4, 5, 6,    -   R¹l is H, a substituted or unsubstituted straight chain,        branched or cyclic lower alkyl, lower alkenyl or lower alkynyl,        or an —Ar or —CH₂)_(n)Ar;-   R⁸ is independently hydrogen, a cephalosporin moiety including but    not limited to one of the following:    -   Where R¹⁰ includes but is not limited to benzylsulfanylmethyl,        phenoxymethyl, hydroxyphenylmethyl, (thiophen-2-yl)methyl,        (2-amino-thiazol-4-yl)-methoxyimino-methyl groups    -   or R⁸ is a penem moiety, including but not limited to one of the        following:-   and wherein the hydroxy group, OR⁸, R⁷ and R^(7′) may be at any    position on the benzene ring.    or Formula III    wherein-   X¹ and X² may be at any position on benzene ring and are    independently hydrogen, a C1-C20 alkyl group or a C₂-C₂₀ alkenyl    group which may be branched or unbranched or a C3-C20 hydrocarbon    group which may be substituted or unsubstituted cycloalkyl group,    chloro, bromo, fluoro, methoxy, ethoxy, dimethylamino,    dimethylaminomethyl;-   Y¹ and Y² may be at any position on benzene ring and are    independently hydrogen, chloro, bromo, fluoro, cyano and nitro    group;-   R⁵, R^(5′), and R⁶ are independently hydrogen, chloro, bromo,    fluoro, cyano, trifluoromethyl, a C1-C20 alkyl group which may be    branched or unbranched or a C3-C20 hydrocarbon group which may be    substituted or unsubstituted cycloalkyl group. Alternatively, R⁵ and    R⁶ are such that together they may form a C5-C15 substituted or    unsubstituted hydrocarbon ring. Alternatively, R^(5′) and R⁵ are    such that together they may form a C3-C15 substituted or    unsubstituted hydrocarbon ring.-   R⁷ and R^(7′) are independently one of the following: hydrogen or    wherein    -   R⁹ is H, substituted or unsubstituted straight chain, branched        or cyclic alkyl, alkenyl or alkynyl, —Ar or —(C₂)_(n)Ar,        —(C₂)_(m)C(═O)R¹¹, —(C₂)_(n)CN, heterocyclyl, heteroaryl,        —(CH₂)_(n)-heterocycyl, —(CH₂)_(n)-heteroaryl,    -   m=1, 2, 3, 4, 5, 6;    -   n=1, 2, 3, 4, 5, 6,    -   R¹¹ is H, a substituted or unsubstituted straight chain,        branched or cyclic lower alkyl, lower alkenyl or lower alkynyl,        or an —Ar or —(CH₂) Ar;-   R⁸ is independently hydrogen, a cephalosporin moiety, including but    not limited to one of the following:    Where    -   R¹⁰ includes but is not limited to benzylsulfanylmethyl,        phenoxymethyl, hydroxy-phenylmethyl, (thiophen-2-yl)methyl,        (2-amino-thiazol-4-yl)-methoxyimino-methyl groups    -   or R⁸ is a penem moiety including but not limited to one of the        following:-   and wherein the hydroxy group, OR⁸, R⁷ and R^(7′) may be at any    position on the benzene ring.

The invention encompasses prophylactic and/or therapeutic compositionscomprising compounds of Formulas I-III and methods of treating orpreventing disease including but not limited to acne, skin infections,pneumonia, cutaneous anthrax, diabetic ulcers, pressure ulcers, softtissue infections, burns, paronychia, mucosal infection, ophthalmicinfections and more particularly diseases associated with infection withCandida albicans, Helicobacter pylori, Bacillus anthracis, Chlamydiapneumoniae, Chlamydia trachomatis, Neisseria gonorrhea, Neisseriameningitidis, HIV, Trichomonas vaginitis, or Giardia, or Trichophytonspp.

In a preferred embodiment the composition further comprises one or moreagents selected from the group consisting of ascorbic acid, ascorbate,zinc chloride, chelating agents, nonionic and anionic surfactants,polyols, gelling agents, boric acid, benzoyl peroxide, polyvivylpyrrolidone, hydrotopes, pH adjusters, skin conditioners, buffers,polyethylene glycols, dyes, aqueous carriers, chlorhexidine, andalcohols.

In another preferred embodiment, the composition comprises triclosan ora derivative of triclosan and additionally at least one compound ofFormulas I-III. In another preferred embodiment, the compositioncomprises at least one compound of Formulas I-III and a lantibiotic. Inanother preferred embodiment, the composition includes EDTA(ethylenediaminetetra acetic acid). In another preferred embodiment, thecomposition comprises at least one compound of Formula I-II andmupirocin or a pharmaceutically acceptable ester or salt.

The invention also encompasses compositions for treating a surface toremove, reduce or inhibit the growth or activity of microorganisms onthe surface. Specific uses for the composition include cleaners forhospitals, nursing homes, daycare centers, dentists' office, anddoctors' offices, coatings for gloves and clothing, sprays to killmicroorganisms (e.g., bacteria, fungi, protozoa, algae, or viruses),deodorants, foot powders, insoles for shoes, paper tissues, wet wipes,sponges, condoms, hand sanitizers, detergents, topical lotions,cosmetics, air duct filters, bandages, containers which carry liquid orbulk food including trucks, cleaners for showers and toilets,humidifiers, teat dips for dairy cows, salves for sores, carpetshampoos, cleaners for medical, dental or laboratory instruments,preservatives for food, chewing gums, lozenges, dental floss, toothpasteadditives and mouthwashes. The invention also provides methods forcleaning and disinfecting a surface at least partly covered by a biofilmcomprising contacting the biofilm with a composition comprising one ormore of the compounds of the invention.

The present invention also includes a method of cleaning anddisinfecting an inert or living surface at least partly covered by abiofilm layer by contacting the biofilm with a composition comprisingone or more of the compounds of the present invention in an amounteffective for either fully or partly removing or releasing the biofilmlayer. The present method also includes a method of inhibiting theformation of a biofilm on a surface comprising contacting a surface witha composition comprising one or more of the compounds of the presentinvention.

An object of the invention is to provide antimicrobial agents andcompositions that are applied to plants by any of a variety ofart-recognized means. For example, the compositions can be applied tothe plants' surface by spraying. Alternatively, the solution can beintroduced injectably into a plant, for example, with a syringe, appliedas a solid fertilized-like preparation for absorption by the roots atthe base of a plant or a solution can be distributed at the base of aplant for root absorption.

It is also an object of the invention to provide compositions for and amethod for removing or killing microorganism from animal carcasses andfresh meat products using solutions comprising compounds of FormulasI-III.

It is also an object of the invention to provide a method of coatingsurfaces such as those of a device, including, medical and laboratorydevices, comprising the steps of applying to at least a portion of thesurface of the device an antimicrobial coating layer comprising at leastone compound of Formulas I-III in a effective concentration to inhibitthe growth or activity of microorganisms (e.g., bacterial, protozoan,fungi, algae, or viruses) and optionally applying one or more resilientprotective coatings over the antimicrobial coating layer. Medicaldevices amenable to treatment by the present invention, include but arenot limited to, urinary catheters, vascular catheters, wound drainagetubes, shunts, cannulas, arterial grafts, soft tissue patches, gloves,stents, tracheal catheters, respirators, wound dressings, sutures, guidewires and prosthetic devices.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1. Efficacy of a composition comprising the compound of Example 9in the wound healing model. A defined inoculum of approximately 10⁵ CFUof methicillin-sensitive Staphylococcus aureus in 20 μl culture mediumwas pipetted into a wound approximately 1 cm² created by removal of theepidermis from the shaved backs of mice. After 24 hours, the compositioncomprising Example 9, placebo control or positive control ointment wasapplied twice daily. Approximately, seventy two hours post-infection,the wound was sampled and appropriate dilutions plated on nutritiveagars for determination of microbial burden. The number of colonyforming units (CFU) of methicillin-sensitive Staphylococcus aureus perwound is shown.

FIG. 2. Efficacy of a composition comprising the compound of Example 9in the wound healing model. A defined inoculum of approximately 10⁵ CFUof methicillin-resistant Staphylococcus aureus in 20 μl culture mediumwas pipetted into a wound approximately 1 cm² created by removal of theepidermis from the shaved backs of mice. After 24 hours, the compositioncomprising Example 9, placebo control or positive control ointment wasapplied twice daily. Approximately, seventy two hours post-infection,the wound was sampled and appropriate dilutions plated on nutritiveagars for determination of microbial burden. The number of colonyforming units (CFU) of methicillin-resistant Staphylococcus aureus perwound is shown.

FIG. 3. Efficacy of a composition comprising the compound of Example 9in the wound healing model. A defined inoculum of approximately 10⁵ CFUof methicillin-sensitive Staphylococcus epidermis in 20 μl culturemedium was pipetted into a wound approximately 1 cm² created by removalof the epidermis from the shaved backs of mice. After 24 hours, thecomposition comprising Example 9, placebo control or positive controlointment was applied twice daily. Approximately, seventy two hourspost-infection, the wound was sampled and appropriate dilutions platedon nutritive agars for determination of microbial burden. The number ofcolony forming units (CFU) of methicillin-sensitive Staphylococcusepidermis per wound is shown.

FIG. 4. Effect of antibiotics on biofilm formation by Staphylococcusaureus 43300. A biofilm-enriched variant of S. aureus 43300(methicillin-resistant) forms stable biofilms on the surface offibronectin-treated coverslips after 8 hours of incubation with liquidbacterial cultures. Biofilms on coverslips are rinsed and incubated inTSB+1% glucose with antibiotics at 64 mg/L for an additional 18 hours.The viable cells on the biofilm are harvested and enumerated by dilutionand plating to determine colony forming units

FIG. 5. Efficacy of a composition comprising the compound of Example 9in the wound healing model. A defined inoculum of approximately 10⁵ CFUof Streptococcus pyrogenes in 20 μl culture medium was pipetted into awound approximately 1 cm² created by removal of the epidermis from theshaved backs of mice. After 24 hours, the composition comprising Example9, placebo control or positive control ointment was applied twice daily.Approximately, seventy two hours post-infection, the wound was sampledand appropriate dilutions plated on nutritive agars for determination ofmicrobial burden. The number of colony forming units (CFU) Streptococcuspyrogenes per wound is shown.

DETAILED DESCRIPTION OF THE INVENTION

Antiseptic or disinfectant compositions of the invention comprising oneor more compounds of the Formulas I, II, or III.

Wherein

-   “a” may be absent or is a single C—C bond-   X¹ and X² may be at any position on benzene ring and are    independently hydrogen, a C1-C20 alkyl group or C₂-C₂₀ alkenyl group    which may be branched or unbranched or a C3-C20 hydrocarbon group    which may be substituted or unsubstituted cycloalkyl group, chloro,    bromo, fluoro, methoxy, ethoxy, dimethylamino, dimethylaminomethyl;-   Y¹ and Y² may be at any position on benzene ring and are    independently hydrogen, chloro, bromo, fluoro, cyano and nitro    group;-   R¹ and R² are independently hydrogen, a C1-C20 alkyl group which may    be branched or unbranched or a C3-C20 hydrocarbon group which may be    substituted or unsubstituted cycloalkyl group. Alternatively, R1 and    R2 are such that together they may form a C5-C20 substituted or    unsubstituted hydrocarbon ring;-   R⁷ and R^(7′) are independently one of the following: hydrogen or    wherein    -   R⁹ is H, substituted or unsubstituted straight chain, branched        or cyclic alkyl, alkenyl or alkynyl, —Ar or —(C₂)_(n)Ar,        —(C₂)_(m)C(═O)R¹l, —(C₂)_(n)CN, heterocyclyl, heteroaryl,        —(C₂)_(n)-heterocycyl, —(CH₂)_(n)-heteroaryl,    -   m=1, 2, 3, 4, 5, 6;    -   n=1, 2, 3, 4, 5, 6;    -   R¹¹ is H, a substituted or unsubstituted straight chain,        branched or cyclic lower alkyl, lower alkenyl or lower alkynyl,        or an —Ar or —(CH₂)_(n)Ar;-   R⁸ is independently hydrogen, a cephalosporin moiety, including but    not limited to one of the following:-   Where R¹⁰ includes but is not limited to benzylsulfanylmethyl,    phenoxymethyl, hydroxy-phenylmethyl, (thiophen-2-yl)methyl,    (2-amino-thiazol-4-yl)-methoxyimino-methyl groups-   or R⁸ is a penem moiety including but not limited to one of the    following:-   and wherein the hydroxy group, OR⁸, R⁷ and R^(7′) may be at any    position on the benzene ring;-   or    wherein-   X¹ and X² may be at any position on benzene ring and are    independently hydrogen, a C1-C20 alkyl group which may be branched    or unbranched or a C3-C20 hydrocarbon group which may be substituted    or unsubstituted cycloalkyl group, chloro, bromo, fluoro, methoxy,    ethoxy, dimethylamino, dimethylaminomethyl;-   Y¹ and Y² may be at any position on benzene ring and are    independently hydrogen, chloro, bromo, fluoro, cyano and nitro    group;-   R³, R^(3′), and R⁴ are independently hydrogen, chloro, bromo,    fluoro, cyano, trifluoromethyl, a C1-C20 alkyl group which may be    branched or unbranched or a C3-C20 hydrocarbon group which may be    substituted or unsubstituted cycloalkyl group. Alternatively, R³ and    R⁴ are such that together they may form a C4-C15 substituted or    unsubstituted hydrocarbon ring. Alternatively, R^(3′) and R³ are    such that together they may form a C3-C15 substituted or    unsubstituted hydrocarbon ring.    -   R⁷ and R^(7′) are independently one of the following: hydrogen        or        wherein    -   R⁹ is H, substituted or unsubstituted straight chain, branched        or cyclic alkyl, alkenyl or alkynyl, —Ar or —(C₂)_(n)Ar,        —(C₂)_(m)C(═O)R¹¹ , —(C₂)_(n)CN, heterocyclyl, heteroaryl,        —(CH₂)_(n)-heterocycyl, —(CH₂)_(n)-heteroaryl,    -   m=1, 2, 3, 4, 5, 6;    -   n=1, 2, 3, 4, 5 , 6,    -   R¹¹ is H, a substituted or unsubstituted straight chain,        branched or cyclic lower alkyl, lower alkenyl or lower alkynyl,        or an —Ar or —(CH₂)_(n)Ar;-   R⁸ is independently hydrogen, a cephalosporin moiety, including but    not limited to one of the following:    -   Where R¹⁰ includes but is not limited to benzylsulfanylmethyl,        phenoxymethyl, hydroxyphenylmethyl, (thiophen-2-yl)methyl,        (2-amino-thiazol-4-yl)-methoxyimino-methyl groups    -   or R⁸ is a penem moiety, including but not limited to one of the        following:-   and the hydroxy group, OR⁸, R⁷ and R^(7′) may be at any position on    the benzene ring.-   or    wherein-   X¹ and X² may be at any position on benzene ring and are    independently hydrogen, a C1-C20 alkyl group or C₂-C₂₀ alkenyl group    which may be branched or unbranched or a C3-C20 hydrocarbon group    which may be substituted or unsubstituted cycloalkyl group, chloro,    bromo, fluoro, methoxy, ethoxy, dimethylamino, dimethylaminomethyl;-   Y¹ and Y² may be at any position on benzene ring and are    independently hydrogen, chloro, bromo, fluoro, cyano and nitro    group;-   R⁵, R^(5′) and R⁶ are independently hydrogen, chloro, bromo, fluoro,    cyano, trifluoromethyl, a C1-C20 alkyl group which may be branched    or unbranched or a C3-C20 hydrocarbon group which may be substituted    or unsubstituted cycloalkyl group. Alternatively, R⁵ and R⁶ are such    that together they may form a C5-C15 substituted or unsubstituted    hydrocarbon ring.

Alternatively, R^(5′) and R⁵ are such that together they may form aC3-C15 substituted or unsubstituted hydrocarbon ring.

-   R⁷ and R^(7′) are independently one of the following: hydrogen or    wherein    -   R⁹ is H, substituted or unsubstituted straight chain, branched        or cyclic alkyl, alkenyl or alkynyl, —Ar or —(C₂)_(n)Ar,        —(C₂)_(m)C(═O)R¹¹, —(C₂)_(n)CN, heterocyclyl, heteroaryl,        —(C₂)_(n)-heterocycyl, —(C₂)_(n)-heteroaryl,    -   m=1, 2, 3, 4, 5, 6;    -   n=1, 2, 3, 4, 5 , 6,    -   R¹¹ is H, a substituted or unsubstituted straight chain,        branched or cyclic lower alkyl, lower alkenyl or lower alkynyl,        or an —Ar or —(CH₂)_(n)Ar;-   R⁸ is independently hydrogen, a cephalosporin moiety, including but    not limited to one of the following:    -   Where R¹⁰ includes but is not limited to benzylsulfanylmethyl,        phenoxymethyl, hydroxyphenylmethyl, (thiophen-2-yl)methyl,        (2-amino-thiazol-4-yl)methoxyimino-methyl groups    -   or R⁸ is a penem moiety including but not limited to one of the        following:-   and wherein the hydroxy group, OR⁸, R⁷ and R^(7′) may be at any    position on the benzene ring.

The core structure of the compounds represented by Formula I wherein ais not present and Formula II can be synthesized by condensation ofalkyl ketones and cyclobutanones with corresponding ortho-substitutedphenols or phenol itself in the presence of acids according to themethods of A. R. Bader and A. D. Kontowicz, J. Am. Chem. Soc., (1954)Vol. 76, 4465-4466 (herein incorporated in its entirety) (Scheme 1 and2). For example, reaction of ketones 1 and 6 with phenol or O-alkylphenols in the presence of acid afford compounds generalized instructure 2, 3, 7 and 8 respectively. Further derivatization of thesecompounds by electrophilic substitution gives more complicatedstructures 4, 5, 9 and 10. The starting material for Formula IIcompounds, 3-substituted (R2=H in 6) and 2,3-disubstitutedcyclobutanones 6 may be prepared according to the methods of E. V.Dehmlov and S. Buker, Chem. Ber. (1993), Vol. 126, 2759-2763; R. L.Danheiser, S. Savariar and D. D. Cha, Org. Synth., Coll. Vol. VIII,(1993), 82 and C. Scmit, J. Falmagne, J. Escudero, H. Vanlierde and L.Chosez, Org. Synth., Coll. Vol. VIII, (1993) 306, all of which areherein incorporated in their entirety by reference.

The core structure of the compounds represented by Formula I with a as asingle bond can be synthesized by following the synthetic routedescribed in Scheme 3. Metallation of bromide 12 derived frombromination of 11, followed by double addition to aliphatc esters,affords tertiary alcohol 13. Metallic alkylation or reduction of 13gives 14, which can be converted into bisphenol 15 by demethylation.

Synthesis of compounds represented by Formula III may be achievedthrough the synthetic routes illustrated in Scheme 4 and 5.Simmons-Smith cyclopropanation of olefins 17, derived from the doubleaddition of methoxy-aryl Grinard reagents 16 to aliphatic estersaccording to the methods of E. C. Friedrich and F. Niyati-Shirkhodaee,J. Org. Chem., (1993), 56, 2202; S. J. Gould, B. Shen, and Y. G.Whittle, J. Am. Chem. Soc., (1989), 111, 7932 (which are hereinincorporated in their entirety by reference), affords intermediates 18,which may be demethylated to compounds 19. Compounds with moresubstituents on cyclopiopane ring may be synthesized by following thesynthetic route in Scheme 5. Benzophenone derivatives 21 can betransformed into carbenoid precursors 23 by the reaction withtolylsulfonyl hydrazine followed by the treatment with a base. Additionof the carbenoids, generated from the decomposition of 23 undercatalytic condition, to alkenes affords the cyclopropane core structure24, which may be converted into bisphenol 25 by demethylation. Furthermodification of 19 and 25 to multi-substituted bisphenols 20 and 26 maybe achieved by electrophilic substitution reactions.

β-Lactam bisphenol conjugates (R7, R7′ are H, R8 is β-lactam moiety inFormula I, II and III) may be synthesized by incorporating bisphenolsrepresented by Formula I, II and III (R8 =H) into β-lactams, forexample, 27 and 29 by using the methods of Herberger, P. M. and Demuth,T. P. in “Resolving The Antibiotic Paradox”, ed. by Rosen and Mabashery,page 239,(1998) (which is hereby incorporated in its entirety byreference) as exemplified in Scheme 6.

Synthesis of specific compounds of Formula I with a as a single bond isillustrated in Scheme 7. 3,3′-Dimethoxydiphenyl 31 is converted intobromide 32 by the reaction with N-bromosuccinimide. Metallation of 32with n-butyl lithium, followed by addition to ethyl caproate, giveintermediate 33, which is reduced by triethylsilane into 34. Thetreatment of 34 with boron tribromide gave the target compound 35.

Specific compounds represented by Formula II of the present inventioncan be synthesized from substituted cyclobutanones, as exemplified inScheme 8. Reactions of cyclobutanone 36 with O-cresol and phenol givebisphenols 37 and 39 respectively. Treatment of 37 and 39 with sulfurylchloride affords chloronated bisphenols 38 and 40.

Specific compounds depicted in Formula III of the present invention canbe prepared from 4-methoxyphenyl magnesium bromide or its alkylderivatives. The preparation of some key intermediates and final NCEsare described in Scheme 9 and 10. The addition reaction of Grinardreagent 41 to ethyl caproate, followed by simultaneous elimination,affords olefin 42. Simmons-Smith reaction of 42 gives 43, which can beconverted into bisphenol 44 by the reaction with boron tribromide.Chlorination of 44 with sulfuryl chloride give 45, and furtherchlorination give trichloride 46 (Scheme 9). Similarly, compound 50 canbe synthesized from Grinard reagent 47 by following the approachdepicted in Scheme 10.

The numbering of carbons in the compounds of the invention is accordingto those well known in the art and is summarized in the followingexample.

In a preferred embodiment of Formula I, R⁷, R^(7′) and R⁸ are hydrogenand R⁸O— and HO— are respectively at position 4 and 4′. In anotherpreferred embodiment of Formula I, X¹ and X² are respectively atposition 3 and 3′, and are independently hydrogen, methyl, ethyl,isopropyl, cyclopropyl or chloro group. In another preferred embodimentof the invention, Y¹ and Y² are respectively at position 5 and 5′, andare independently hydrogen, chloro, bromo, fluoro, cyano group.

In yet another embodiment of Formula I, R¹ and R² are independentlyhydrogen, C1-C10 alkyl group which may be branched or unbranched, orC3-C10 hydrocarbon group which may be substituted or unsubstitutedcycloalkyl group or R¹ and R² when taken together with the carbons towhich they are attached represent C5-C10 cyclic hydrocarbons withsubstituents selected from the group consisting of hydrogen, methyl,ethyl, isopropyl and tert-butyl group at any positions on the ring.

A preferred compound of Formula I is a compound having the followingFormula

wherein

X¹ and X² are independently hydrogen, methyl, ethyl, isopropyl,cyclopropyl or chloro group;

Y¹ and Y² are independently hydrogen, chloro, bromo, fluoro, cyano ornitro group;

R¹, R² are independently hydrogen, C1-10 alkyl group which may bebranched or unbranched, or C3-C10 hydrocarbon group which may be asubstituted or unsubstituted cycloalkyl group; R¹ and R² when takentogether with the carbons to which are attached a C5-C10 cyclichydrocarbon with substituents selected from the group consisting ofhydrogen, methyl, ethyl, isopropyl and tert-butyl group at any positionson the ring.

A preferred composition including a preferred compound of Formula I isan antimicrobial composition comprising a compound the following Formula

wherein

-   -   X¹ and X² are independently hydrogen, methyl, ethyl, isopropyl,        cyclopropyl, or chloro group;

Y¹ and Y² are independently hydrogen, chloro, bromo, fluoro, cyano ornitro group;

R¹, R² are independently hydrogen, methyl, ethyl, propyl, butyl, pentyl,hexyl, heptyl or octyl, or R¹ and R² when taken together with thecarbons to which they are attached represent cyclic hydrocarbonsselected from the group consisting of cyclopentylidene,cycloheptylidene, cyclooctylidene or 4-substituted-cyclohexylidenewherein the substituents are selected from the group consisting ofhydrogen, methyl, ethyl, isopropyl and tert-butyl group; and

-   an acceptable carrier.

In a preferred embodiment of Formula II, R⁷, R^(7′) and R⁸ are hydrogenand R⁸O— and hydroxyl groups are respectively at position 4 and 4′. Inanother preferred embodiment of Formula II, X¹ and X² are respectivelyat position 3 and 3′, and are independently hydrogen, methyl, ethyl,isopropyl, cyclopropyl or chloro group. In another preferred embodimentof Formula II of the invention, Y¹ and Y² are respectively at position 5and 5′, and are independently hydrogen, chloro, bromo, fluoro, cyanogroup.

A preferred compound of Formula II is a compound of the followingformula

wherein

-   X¹ and X² are independently hydrogen, methyl, ethyl, isopropyl,    cyclopropyl or chloro group;-   Y¹ and Y² are independently hydrogen, chloro, bromo, fluoro, cyano    group;

R³, R³′ and R⁴ are independently hydrogen, C1-C10 alkyl group which maybe branched or unbranched, or C3-C10 hydrocarbon group which may besubstituted or unsubstituted cycloalkyl group, or R³ and R3′ when takentogether with the carbons to which they are attached represent C3-C10cyclic hydrocarbons with substituents selected from the group consistingof hydrogen, methyl, ethyl, isopropyl, tert-butyl and neopentyl group atany positions on the ring.

Another preferred compound of Formula II is a compound of the followingformula

wherein

-   -   X¹ and X² are independently hydrogen, methyl, ethyl, isopropyl,        cyclopropyl or chloro group;

Y¹ and Y² are independently hydrogen, chloro, bromo, fluoro, cyano ornitro group; and

R³ is hydrogen, methyl, ethyl, n-propyl, n-butyl, tert-butyl,2-methylpropyl, cyclopropyl, cyclobutyl, spirocyclopropyl andspirocyclobutyl group.

In yet another embodiment of the invention of Formula II, R³, R³′ and R⁴are independently hydrogen, C1-C10 alkyl group which may be branched orunbranched, or C3-C10 hydrocarbon group which may be substituted orunsubstituted cycloalkyl group, or R³ and R³′ when taken together withthe carbons to which they are attached represent C3-C10 cyclichydrocarbons with substituents selected from the group consisting ofhydrogen, methyl, ethyl, isopropyl and tert-butyl group at any positionson the ring.

In a preferred embodiment of Formula III, R⁷, R^(7′) and R⁸ areindependently hydrogen and R⁸O— or hydroxyl group and are at position 4and 4′. In another preferred embodiment of Formula III, X¹ and X² arerespectively at position 3 and 3′, and are independently hydrogen,methyl, ethyl, isopropyl, cyclopropyl or chloro group. In anotherpreferred embodiment of Formula III of the invention, Y¹ and Y² arerespectively at position 5 and 5′, and are independently hydrogen,chloro, bromo, fluoro, cyano group.

A preferred compound of Formula III is a compound of the followingformula

wherein

-   X¹ and X² are independently hydrogen, methyl, ethyl, isopropyl,    cyclopropyl or chloro group;-   Y¹ and Y² are independently hydrogen, chloro, bromo, fluoro, cyano    group;

R⁵, R⁵′ and R⁶ are independently hydrogen, C1-C10 alkyl group which maybe branched or unbranched, or C3-C10 hydrocarbon group which may besubstituted or unsubstituted cycloalkyl group, or R⁵ and R⁵′ when takentogether with the carbons to which they are attached represent C3-C10cyclic hydrocarbons with substituents selected from the group consistingof hydrogen, methyl, ethyl, isopropyl and tert-butyl group at anypositions on the ring.

Another preferred compound of Formula III is a compound of the followingformula

wherein

X¹ and X² are independently hydrogen, methyl, ethyl, isopropyl or chlorogroup;

Y¹ and Y² are independently hydrogen, chloro, bromo, fluoro, cyano ornitro group;

R⁴ is hydrogen, methyl, ethyl, n-propyl, n-butyl, tert-butyl,2-dimethylpropyl, cyclopropyl, cyclobutyl, spirocyclopropyl andspirocyclobutyl group; and

Z is hydrogen, bromo, chloro, fluoro, methyl, ethyl, or cyano.

In yet another embodiment of Formula III of the invention, R⁵, R⁵′ andR⁶ are independently hydrogen, C1-C10 alkyl group which may be branchedor unbranched, or C3-C10 hydrocarbon group which may be substituted orunsubstituted cycloalkyl group, or R⁵ and R5′ when taken together withthe carbons to which they are attached represent C3-C10 cyclichydrocarbons with substituents selected from the group consisting ofhydrogen, methyl, ethyl, isopropyl and tert-butyl group at any positionson the ring.

The term disinfectant is used herein to mean a composition applied toinanimate objects used to destroy, reduce or retard the growth, activityor infectivity of microorganisms, including but not limited to bacteria,fungi, protozoa, algae, and viruses on the inanimate objects. The termantiseptic is used herein to mean a composition applied to animals orplants that destroys inhibits or stops the growth, activity orinfectivity of microorganisms including but not limited to bacteria,fungi, protozoa, algae, and viruses, and in one embodiment is used totreat or prevent a disease caused by or associated with an infectiousmicroorganism. The term antimicrobial is used herein to mean acomposition used as an antiseptic and/or a disinfectant.

In a preferred embodiment, the antiseptic composition will comprisesabout 0.05% to about 25%, preferably about 0.5 % to 25% and mostpreferably about 0.5% to 20% of one or more of the compounds of FormulasI-III. The compositions also can be formulated as concentrates that arediluted before use.

In a preferred embodiment, the disinfectant composition will comprisesabout 5% to about 50%, preferably about 15% to 50% and most preferablyabout 15% to 40% of one or more of the compounds of Formulas I-III. Thecompositions also can be formulated as concentrates that are dilutedbefore use.

In a preferred embodiment both the antiseptic and disinfectantcompositions further comprise one or more agents selected from the groupconsisting of zinc chloride, ascorbic acid, ascorbate, nonionic andanionic surfactants, alcohols, chelators, polyols, gelling agents,hydrotopes, pH adjusters, skin conditioners chlorhexidine, dyes andfragrances. The agents are present in a sufficient amount to performtheir intended function and do not adversely affect the antimicrobialefficacy of the composition.

Suitable surfactants are those which are reasonably stable andpreferably form suds through the pH range of the compositions.Surfactants useful as sudsing agents may be soaps, and anionic,nonionic, cationic, zwitterionic and amphoteric organic syntheticdetergents, and compatible mixtures thereof. Surfactants of these typesare described more fully in U.S. Pat. No. 3,959,458 issued to Agricola,Briner, Granger & Widder on May 25, 1976 and U.S. Pat. No. 3,937,807issued to Haefele on Feb. 10, 1976, both of which are incorporatedherein by reference in their entirety. Such surfactants are generallysubject in the compositions of the subject invention at a level of fromabout 0% to about 10%. Surfactants may also be used as solubilizingagents to help retain sparingly soluble components, e.g., some flavoringagents, in solutions. Surfactants suitable for this purpose includepolysorbates and poloxamers.

Suitable chelators include, but are not limited to EDTA, CaEDTA,CaNa₂EDTA, EGTA (ethylene glycol bis(β-aminoethylether)N,N,N′,N′-tetraacetic acid) and citrate.

Suitable alcohols include, but are not limited to, propylene glycol,1,3-propanediol, 1,2-butanediol, PEG (polyethylene glycol) 200, PEG 400,PEG 600, PEG 900, PEG 3350, PEG 1450, PEG 6000, PEG 8000, glycerol, 1,4butanediol, C₁₋₆ alcohols e.g., ethanol and isopropanol, methanol,n-butyl alcohol, tert-butyl alcohol, or mixtures thereof.

The following are non-limiting examples of gelling agents that can beused in the present invention. In particular, the following compoundsboth organic and inorganic, act primarily by thickening or gelling theaqueous portion of the composition: acacia, acrylates/steareth-20methacrylate copolymer, agar, algin, alginic acid, ammonium chloride,ammonium sulfate, amylopectin, bentonite, C₉₋₁₅ alcohols, calciumacetate, calcium alginate, calcium carrageenan, calcium chloride,caprylic alcohol, carbomer 910, carbomer 934, carbomer 934P, carbomer940 carbomer 941, carboxymethyl hydroxyethylcellulose, carboxymethylhydroxypropyl guar, carrageenan, cellulose, cellulose gum, cetearylalcohol, cetyl alcohol, corn starch, damar, dextrin, dibenzylidinesorbitol, ethylene dihydrogenated tallowamide, ethylenedioleamide,ethylene distearamide, gelatin, guar gum, guar hydroxypropyltrimoniumchloride, hectorite, hyaluronic acid, hydrated silica, hydroxybutylmethylcellulose, hydroxyethylcellulose, hydroxyethyl ethylcellulose,hydroxyethyl stearamide-MIPA (monoisopropanolamine),hydroxypropylcellulose, hydroxypropyl guar, hydroxypropylmethylcellulose, isocetyl alcohol, isostearyl alcohol, karaya gum, kelp,lauryl alcohol, locust bean gum, magnesium aluminum silicate, magnesiumsilicate, magnesium trisilicate, methoxy PEG-22/dodecyl glycolcopolymer, methylcellulose, microcrystallinc cellulose, montmorillonite,myristyl alcohol, oat flour, oleyl alcohol, palm kernel alcohol, pectin,PEG-200, PEG400, PEG500, PEG600, polyacrylic acid, polyvinyl alcohol,potassium alginate, potassium aluminum polyacrylate, potassiumcarrageenan, potassium chloride, potassium sulfate, potato starch,propylene glycol alginate, sodium acrylate/vinyl alcohol copolymer,sodium carboxymethyl dextran sodium carrageenan, sodium cellulosesulfate, sodium chloride, sodium polymethacrylate, sodiumsilicoaluminate, sodium sulfate, stearalkonium bentonite, stearalkoniumhectorite, stearyl alcohol, tallow alcohol, TEA(triethanolamine)-hydrochloride, tragacanth gum, tridecyl alcohol,trimethamine magnesium aluminum silicate, wheat flour, wheat starch,xanthan gum, and mixtures thereof.

The following additional non-limiting examples of gelling agents actprimarily by thickening the nonaqueous portion of the composition:abietyl alcohol, acrylinoleic acid, aluminum behenate, aluminumcaprylate, aluminum dilinoleate, aluminum distearate, aluminumisostearates/laurates/palmitates or stearates, aluminumisostearates/myristates, aluminum isostearates/palmitates, aluminumisostearates/stearates, aluminum lanolate, aluminummyristates/palmitates, aluminum stearate, aluminum stearates, aluminumtristearate, beeswax, behenamide, behenyl alcohol,butadiene/acrylonitrile copolymer, calcium behenate, calcium stearate,candelilla wax, carnauba, ceresin, cholesterol, cholesterylhydroxystearate, coconut alcohol, copal, diglyceryl stearate malate,dihydroabietyl alcohol, dimethyl lauramine oleate, dodecanedioicacid/cetearyl alcohol/glycol copolymer, erucamide, ethylcellulose,glyceryl triacetyl hydroxystearate, glyceryl tri-acetyl ricinoleate,glycol dibehenate, glycol dioctanoate, glycol distearate, hexanedioldistearate, hydrogenated C6-14 olefin polymers, hydrogenated castor oil,hydrogenated cottonseed oil, hydrogenated lard, hydrogenated menhadenoil, hydrogenated palm kernel glycerides, hydrogenated palm kernel oil,hydrogenated palm oil, hydrogenated polyisobutene, hydrogenated soybeanoil, hydrogenated tallow amide, hydrogenated tallow glyceride,hydrogenated vegetable glyceride, hydrogenated vegetable glycerides,hydrogenated vegetable oil, hydroxypropylcellulose, isobutylene/isoprenecopolymer, isocetyl stearoyl stearate, Japan wax, jojoba wax, lanolinalcohol, lauramide, methyl dehydroabietate, methyl hydrogenatedrosinate, methyl rosinate, methylstyrene/vinyltoluene copolymer,microcrystalline wax, montan acid wax, montan wax, myristyleicosanol,myristyloctadecanol, octadecene/maleic anhydride copolymer, octyldodecylstearoyl stearate, oleamide, oleostearine, ouricury wax, oxidizedpolyethylene, ozokerite, palm kernel alcohol, paraffin, pentaerythritylhydrogenated rosinate, pentaerythrityl rosinate, pentaerythrityltetraabietate, pentaerythrityl tetrabehenate, pentaerythrityltetraoctanoate, pentaerythrityl tetraoleate, pentaerythrityltetrastearate, phthalic anhydride/glycerin/glycidyl decanoate copolymer,phthalic/trimellitic/glycols copolymer, polybutene, polybutyleneterephthalate, polydipentene, polyethylene, polyisobutene, polyisoprene,polyvinyl butyral, polyvinyl laurate, propylene glycol dicaprylate,propylene glycol dicocoate, propylene glycol diisononanoate, propyleneglycol dilaurate, propylene glycol dipelargonate, propylene glycoldistearate, propylene glycol diundecanoate, PVP(polyvinylpyrrolidone)/eicosene copolymer, PVP/hexadecene copolymer,rice bran wax, stearalkonium bentonite, stearalkonium hectorite,stearamide, stearamide DEA (diethonolamine)-distearate, stearamideDIBA-stearate, stearamide MEA (monothanolamine)-stearate, stearone,stearyl alcohol, stearyl erucamide, stearyl stearate, stearyl stearoylstearate, synthetic beeswax, synthetic wax, trihydroxystearin,triisononanoin, triisostearin, triisononanoin, triisostearin,tri-isostearyl trilinoleate, trilaurin, trilinoleic acid, trilinolein,trimyristin, triolein, tripalmitin, tristearin, zinc laurate, zincmyristate, zinc neodecanoate, zinc rosinate, zinc stearate, and mixturesthereof.

The hydrotrope, if present at all, is present in an amount of about 0.1%to about 30%, and preferably about 0.5% to about 25%, by weight of thecomposition. A hydrotrope is a compound that has the ability to enhancethe water solubility of other compounds. A hydrotrope lacks surfactantproperties, and typically is a short-chain alkyl aryl sulfonate.Specific examples of hydrotropes include, but are not limited to, sodiumcumene sulfonate, ammonium cumene sulfonate, ammonium xylene sulfonate,potassium toluene sulfonate, sodium toluene sulfonate, sodium xylenesulfonate, toluene sulfonic acid, and xylene sulfonic acid. Other usefulhydrotropes include sodium polynaphthalene sulfonate, sodium polystyrenesulfonate, sodium methyl naphthalene sulfonate, and disodium succinate.

Basic pH adjusters include, but are not limited to, are ammonia; mono-,di-, and tri-alkyl amines; mono-, di, and tri-alkanolamines; alkalimetal and alkaline earth metal hydroxides; and mixtures thereof.However, the identity of the basic pH adjuster is not limited, and anybasic pH adjuster known in the art can be used. Specific, nonlimitingexamples of basic pH adjusters are ammonia; sodium, potassium, andlithium hydroxide; monoethanolamine; triethylamine; isopropanolamine;diethanolamine; and triethanolamine acidic pH adjusters include but arenot limited to the mineral acids and polycarboxylic acids. Nonlimitingexamples of mineral acids are hydrochloric acid, nitric acid, phosphoricacid, and sulfuric acid. Nonlimiting examples of polycarboxylic acidsare citric acid, glycolic acid, and lactic acid. The identity of theacidic pH adjuster is not limited and any acidic pH adjuster known inthe art, alone or in combination, can be used.

Skin conditioners include but are not limited to, emollients, such as,cetyl myristate, glyceryl dioleate, isopropyl myristate, lanolin, methyllaurate, PPG (polypropylene glycol)-9 laurate, soy stearyl, octylpalmitate, and PPG-5 laurate, for example. The skin conditioner also canbe a humectant, for example, glucamine and pyridoxine glycol, forexample. Occlusive skin conditioners, for example, aluminum lanolate,corn oil, methicone, coconut oil, stearyl stearate, phenyl trimethicone,trimyristin, olive oil, and synthetic wax, also can be used.Combinations of the classes of skin conditioners, in addition tomiscellaneous skin conditioners known to persons skilled in the art,alone or in combination can be used. Nonlimiting examples ofmiscellaneous skin conditioners include aloe, cholesterol, cystine,keratin, lecithin, egg yolk, glycine, PPG-12, retinol, salicylic acid,orotic acid, vegetable oil, and soluble animal collagen. The skinconditioners can be used alone, or in combination with a skinprotectant, like petroleum, cocoa butter, calamine, and kaolin, forexample. A skin protectant also can be used alone. Additional examplesof skin conditioners and protectants can be found in “CTFA CosmeticIngredient Handbook,” J. M. Nikitakis, ed., The Cosmetic, Toiletry andFragrance Association, Inc., Washington, D.C. (1988) (hereafter CTFAHandbook), pages 79-85, incorporated herein by reference.

Disinfecting a surface can be accomplished by any conventional methodused to clean surfaces such as by means of a brush, cloth or spongewetted with the treating solution or by immersion of the surface in thetreating solution or contacting the surface with an automatic washer fora period of time sufficient to remove, retard or reduce contamination.Any surface may be treated, including but not limited to steel, wood, orplastic. The treating solution may be sprayed on as a wet or dryformulation. In some instances time release formulations may find use,particularly for applications to surface subject to recontamination.

It is also an object of the invention to provide a composition for and amethod for removing or killing microorganisms on animal carcasses andfresh meat products using solutions comprising one or more of compoundsof Formulas I-III. The solution (or other liquid carrier such asemulsion or suspension) of the invention is used as a dip or as a sprayor as a combination of these applications. In a typical method fordisinfecting poultry carcasses or poultry carcass pieces, for example,the carcasses or pieces are washed after evisceration, immersed in achilling tank and then removed from the tank. An optional wash of thecarcasses or pieces may follow these processing steps. In the practiceof the invention, the carcasses or carcass pieces are contacted with thedisinfectant solution during the initial washing after evisceration,during the chill tank immersion period or during a spray wash removalfrom the chill tank. The disinfectant solution of the invention may alsobe used in more than one of these processing steps. A food-grade wettingagent such as alkylphenoxypoly(ethylene oxide), a poly (ethyleneoxide/propylene oxide)block copolymer, an alkylbenzene sulfonic acid, adioctylsolfosuccinate and mixtures of these may be added to the solutionto facilitate contact with the meat surfaces. The solution may alsocontain effective amounts of a food-grade thickener such as xanthum gum,or alginic acid preferably one sufficient to achieve a final solution(i.e., liquid) viscosity of from about 5 cps to about 50 cps at roomtemperature, for spray applications.

It is also an object of the invention to provide a method of coating adevice comprising the steps of applying to at least a portion of thesurface of the device an antimicrobial coating layer comprising one ormore of compounds of Formulas I-III in a effective concentration toinhibit the growth of microorganisms (e.g. bacterial, fungi, protozoa,algae or virus) and optionally applying resilient protective coatingover the antimicrobial coating layer.

When the device comprises plastic (or other resin), the antimicrobialcomprising one or more of compounds of Formulas I-III may beincorporated into the plastic material in an effective concentration toinhibit the growth or activity of harmful microorganisms and to protectthe plastic from degradation by harmful microorganisms. Devices composedof a variety of materials, e.g. metal, that are treated with the presentcompounds/compositions can be used to make a wide variety of productssuch as furniture, medical devices, laboratory equipment, tubing, foodhandling trays, shower curtains. The present compositions may beincorporated in the material from which the device is fabricated or maybe used to treat the surface of the device. Medical devices encompassedby the present invention, include but are not limited to, urinarycatheters, vascular catheters, drainage bags, colostomy pouches,ileostomy pouches, wound drainage tubes, arterial grafts, soft tissuepatches, gloves, shunts, stents, tracheal catheters, wound dressings,sutures, guide wires and prosthetic devices

Disinfectant compositions comprising at least one of compounds of theinvention can be applied topically to fabrics, to natural and syntheticfibers or can be incorporated directly onto synthetic fibers to impartantimicrobial activity to the fibers or fabrics made from the fibers.Fiber or fabric products include but are not limited to air filters,surgical gauze, padding on wound dressings, mattress covers, cribcovers, sailboat sails, tents, draw sheets, and hospital clothing suchas physician coats and nurse uniforms.

The compounds of this invention can be administered as treatment forbacterial, protozoan, viral, or fungal infections or colonization(including biofilms comprising one or more microbes) by any means thatproduces contact of the active agent with the bacteria, protozoa, virusor fungus in the living body of an animal or plant or on the surface ofanimal carcasses or nonliving objects. They can be administered by anyconventional means available for use in conjunction withpharmaceuticals, either as individual therapeutic agents or in acombination of therapeutic agents.

The present compounds can be administered alone, but generallyadministered with a pharmaceutical carrier selected on the basis of thechosen route of administration and standard pharmaceutical practice. Ina preferred embodiment the pharmaceutical carrier is slightly polar. Ina more preferred embodiment, the formulation comprises 5-35% of acompound of Formula I in PEG 600, PEG 400, or PEG 200. In anotherpreferred formulation, the formulation comprises 5-35% of a compound ofFormula I-III in 10-40% PEG3350/60-90% PEG 400. In yet another preferredformulation, the formulation comprises 5-35% of a compound of FormulaI-III in 5-35% PEG 8000/65-95% PEG200 In another preferred formulation,the formulation comprises 5-35% of a compound of Formula I-III in 10-45%propylene glycol/50-75% ethanol or isopropanol. In another preferredembodiment the formulation comprises 5-35% of a compound of FormulaI-III in PEG 200/0.1-1% ascorbate. In another preferred embodiment, thecomposition comprises a compound of Formula I-III and benzoyl peroxide.In another preferred embodiment the composition comprises a compound ofFormula I-III and boric acid. In another preferred embodiment thecomposition comprises a compound of Formula I-III and polyvinylpyrrolidone.

The compounds are of course given by forms suitable for eachadministration route. For example, they are administered in tablets orcapsule form, by injection, inhalation, eye lotion, ointment, foams,suppository, etc. administration by injection, infusion, inhalationtopically, vaginally or rectally. Oral or topical administration ispreferred. The compounds of the invention are useful for the treatmentof infections in hosts, especially mammals, including humans, inparticular in humans and domesticated animals (including but not limitedto equines, cattle, swine, sheep, poultry, feline, canine and pets ingeneral) and plants. The compounds may be used, for example, for thetreatment of infections of skin, mouth, eye, the respiratory tract, theurinary/reproductive tract, and soft tissues and blood, especially inhumans.

The compounds may be used in combination with one or more therapeuticpartners for the treatment of infections. The term “therapeutic partner”or “therapeutic agent” as used herein and in the claims includes but isnot limited to antibiotic (for example, tobramycin, cephalosporin),steroids, vaccines, anti-oxidants, zinc chloride, ascorbic acid,ascorbate, dextran sulfate, non-steroidal anti-inflammatories, antacids,antibodies, chelators, interferons, protease, glucosidases, pectinase,amylase, lipase and/or cytokines.

Examples of therapeutic partners that may be co-administered with thecompounds according to the invention include, but are not limited tonystatin, amphotericin B, griseofulvin, flucytosine, potassium iodide,polymixin B, imidazole (i.e. clotrimazole, miconazole, ketoconazole),tolnaftrate, cyclophosamide, ascorbic acid, ascorbate, meprazole,dextran sulfate, bismuth, histamine H2 receptor antagonist,chlorhexidine, pseudosmic acid, boric acid, polyvinyl pyrrolidone,benzoyl peroxide, serine protease, glucosidase, lanthioninebacteriocins, clarithromycin, omeprazole, metronidazole, quinacrinehydrochloride, norfloxacin, ciprofloxacin, levofloxacin, enoxacin,triclosan, clarithromycin, tobramycin, cephalosporin, furazolidone,tiniadazole, tetracycline, Lansoprazole imipenem, meropenem, biapenem,aztreonam, latamoxef (MOXALACTAM™), and other known beta-lactamantibiotics, benzylpenicillin, phenoxymethylpenicillin, carbenicillin,azidocillin, propicillin, ampicillin, amoxycillin, epicillin,ticarcillin, cyclacillin, pirbenicillin, azlocillin, mezlocillin,sulbenicillin, piperacillin, and other known penicillins. Thepenicillins may be used in the form of pro-drugs thereof, for example asin vivo hydrolysable esters, for example the acetoxymethyl,pivaloyloxymethyl, alpha-ethoxycarbonyloxyethyl and phthalidyl esters ofampicillin, benzylpenicillin and amoxycillin; as aldehyde or ketoneadducts of penicillins containing a 6-alpha-aminoacetamido side chain(for example hetacillin, metampicillin and analogous derivatives ofamoxicillin); and as alpha-esters of carbenicillin and ticarcillin, forexample the phenyl and indanyl alpha-esters. Cephalosporins that may betherapeutic partners with the compounds according to the inventioninclude, but are not limited to, cefatrizine, cephaloridine,cephalothin, cefazolin, cephalexin, cephacetrile, cephapirin,cephamandole nafate, cephradine, 4-hydroxycephalexin, cephaloglycin,cefoperazone, cefsulodin, ceftazidime, cefuroxime, cefinetazole,cefotaxime, ceftriaxone, and other known cephalosporins. Lanthioninebacteriocins that may be therapeutic partners with the compounds of thisinvention, include, but are not limited to, nisin, subtilin, subtilin168, duramycin, cinnamycin, ancovenin, Pep 5, epidermin, andgallidermin. All of therapeutic partners may be used in the form ofpro-drugs thereof. In a preferred embodiment the composition comprisesat least one compound of Formulas I-III and at least one lanthioninebacteriocin. In another preferred embodiment the composition comprises achelator. In yet another preferred embodiment, the compositionscomprises at least on compound of Formulas I-III and at least one of thefollowing: chlorhexidine, mupirocin, boric acid, benzoyl peroxide,polyvinyl pyrrolidone or a lanthionine bacteriocin.

When the compounds of the invention are co-administered with atherapeutic partner, the ratio of the amount of the compound accordingto the invention to the amount of the therapeutic partner may varywithin a wide range. The said ratio may, for example, be from 100:1 to1:100; more particularly, it may be, for example, from 2:1 to 1:30. Theamount of the therapeutic will normally be approximately similar to theamount in which it is conventionally used per se, for example from about50 mg, advantageously from about 62.5 mg, to about 3000 mg per unitdose, more usually about 125, 250, 500 or 1000 mg per unit dose.

It is generally advantageous to use a compound according to theinvention in admixture or conjunction with one or more therapeuticpartners that can result in a synergistic effect. The compounds of theinvention and the therapeutic partner(s) can be administered separatelyor in the form of a single composition containing the activeingredients. The compounds of the invention and the therapeuticpartner9s) may be administered simultaneously or sequentially. Examplesof simultaneous administration include where two or more compounds,compositions, or vaccines which may be the same or different, areadministered in the same or different formulation or are administeredseparately, e.g. in a different or the same formulation but within ashort time (such as minutes or hours) of each other. Examples ofsequential administration include where two or more compounds,compositions or vaccines which may be the same or different are notadministered together within a short time of each other, but may beadministered separately at intervals of for example days, weeks, monthsor years.

Formulations of the present invention include those suitable for oral,nasal, topical, transdermal, ophthalmic, buccal, sublingual, rectal,vaginal and/or parenteral administration. The formulations mayconveniently be presented in unit dosage form and may be prepared by anymethods well known in the art of pharmacy. The amount of activeingredient which can be combined with a carrier material to produce asingle dosage form will generally be that amount of the compound whichproduces a therapeutic effect. Generally, out of one hundred per cent,this amount will range from about 1 per cent to about ninety-ninepercent of active ingredient, preferably from about 5 per cent to about70 per cent, most preferably from about 10 per cent to about 30 percent.

Methods of preparing these formulations or compositions include the stepof bringing into association a compound of the present invention withthe carrier and, optionally, one or more accessory ingredients. Ingeneral, the formulations are prepared by uniformly and intimatelybringing into association a compound of the present invention withliquid carriers, or finely divided solid carriers, or both, and then, ifnecessary, shaping the product.

Formulations of the invention suitable for oral administration may be inthe form of capsules, cachets, pills, tablets, lozenges (using aflavored basis, usually sucrose and acacia or tragacanth), chewing gum,powders, granules, or as a solution or a suspension in an aqueous ornon-aqueous liquid, or as an oil-in-water or water-in-oil liquidemulsion, or as an elixir or syrup, or as pastilles (using an inertbase, such as gelatin and glycerin, or sucrose and acacia) and/or asmouth washes and the like, each containing a predetermined amount of acompound of the present invention as an active ingredient. A compound ofthe present invention may also be administered as a bolus, electuary orpaste.

In solid dosage forms of the invention for oral administration(capsules, tablets, pills, dragées, powders, granules and the like), theactive ingredient is mixed with one or more pharmaceutically acceptablecarriers, such as sodium citrate or dicalcium phosphate, and/or any ofthe following: fillers or extenders, such as starches, lactose, sucrose,glucose, mannitol, and/or silicic acid; binders, such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone,sucrose and/or acacia; humectants, such as glycerol; disintegratingagents, such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate; solutionretarding agents, such as paraffin; absorption accelerators, such asquaternary ammonium compounds; wetting agents, such as, for example,cetyl alcohol and glycerol monostearate; absorbents, such as kaolin andbentonite clay; lubricants, such a talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate, andmixtures thereof, and coloring agents. In the case of capsules, tabletsand pills, the pharmaceutical compositions may also comprise bufferingagents. Solid compositions of a similar type may also be employed asfillers in soft and hard-filled gelatin capsules using such excipientsas lactose-or milk sugars, as well as high molecular weight polyethyleneglycols and the like.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared usingbinder (for example, gelatin or hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface-active or dispersing agent. Molded tablets may be made bymolding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

The tablets, and other solid dosage forms of the pharmaceuticalcompositions of the present invention, such as dragées, capsules, pillsand granules, may optionally be scored or prepared with coatings andshells, such as enteric coatings and other coatings well known in thepharmaceutical-formulating art. They may also be formulated so as toprovide slow, controlled or sustained release of the active ingredienttherein using, for example, hydroxypropylmethyl cellulose in varyingproportions to provide the desired release profile, other polymermatrices, liposomes, nanospheres and/or microspheres.

Microspheres and nanospheres for delivery of pharmaceutical substancesare well known (see for example U.S. Pat. No. 5,707,644, U.S. Pat. No.6,207,197, Kumar U. Pham Pharmaceut Sci 3:234, 2000, or Nagahara et al.Antimicrobial Agents and Chemotherapy 42:2492, 1998, all of which arehereby incorporated herewith in their entirety). Matrices used to makemicrospheres or nanospheres include but are not limited to chitosan,poly(L-lactic acid-co-polyglycolic acid) (PLGA), calcium phosphate, poly(L-lactic acid) (PLA), starch, gelatin, dextran, collagen, albumin,alginate, alginate-poly-L-lysine, and adipic anhydride. The selection ofthe composition and size for manufacturing the micro- or nano-spheresdepends upon the route of administration, the desired site ofpreferential absorption and the desired rate of release. In a preferredembodiment the compound is formulated in a micro- or nano-sphere foreffective absorption in nasal cavity, stomach, duodenum, or eye.

They may be sterilized by, for example, filtration through abacteria-retaining filter, or by incorporating sterilizing agents in theform of sterile solid compositions which can be dissolved in sterilewater, or some other sterile injectable medium immediately before use.These compositions may also optionally contain opacifying agents and maybe of a composition that they release the active ingredient(s) only, orpreferentially, in a certain portion of the gastrointestinal tract,optionally, in a delayed manner. Examples of embedding compositionswhich can be used include polymeric substances and waxes. The activeingredient can also be in micro-encapsulated form, if appropriate, withone or more of the above-described excipients.

Liquid dosage forms for oral administration of the compounds of theinvention include pharmaceutically acceptable emulsions, microemulsions,solutions, suspensions, syrups and elixirs. In addition to the activeingredient, the liquid dosage forms may contain inert diluents commonlyused in the art, such as, for example, water or other solvents,solubilizing agents and emulsifiers, such as ethyl alcohol, isopropylalcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylene glycol, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor and sesame oils),glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acidesters of sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar, bismuth, and tragacanth, andmixtures thereof.

Formulations of the pharmaceutical compositions of the invention forrectal or vaginal administration may be presented as a suppository,which may be prepared by mixing one or more compounds of the inventionwith one or more suitable nonirritating excipients or carrierscomprising, for example, cocoa butter, polyethylene glycol, asuppository wax or a salicylate, and which is solid at room temperature,but liquid at body temperature and, therefore, will melt in the rectumor vaginal cavity and release the active compound.

Formulations of the present invention which are suitable for vaginaladministration also include pessaries, tampons, creams, gels, pastes,foams or spray formulations containing such carriers as are known in theart to be appropriate.

Dosage forms for the topical or transdermal administration of compoundsof this invention include powders, sprays, ointments, foams, pastes,creams, lotions, gels, solutions, patches and inhalants. The activecompound may be mixed with a pharmaceutically acceptable carrier, andwith any preservatives, buffers, or propellants which may be required.

The ointments, pastes, creams and gels may contain, in addition toactive compounds of this invention, excipients, such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to compounds of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants, suchas chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons,such as butane and propane.

Transdermal patches have the added advantage of providing controlleddelivery of a compound of the present invention to the body. Such dosageforms can be made by dissolving or dispersing the compound in the propermedium. Absorption enhancers can also be used to increase the flux ofthe compound across the skin. The rate of such flux can be controlled byeither providing a rate controlling membrane or dispersing the activecompound in a polymer matrix or gel.

Ophthalmic formulations, eye ointments, powders, solutions and the like,are also contemplated as being within the scope of this invention.

For administration by inhalation, the compounds for use according to thepresent invention are conveniently delivered in the form of an aerosolspray presentation from pressurized packs or a nebulizer, with the useof a suitable propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of a pressurized aerosol the dosage unitmay be determined by providing a valve to deliver a metered amount.Capsules and cartridges of, e.g., gelatin for use in an inhaler orinsufflator may be formulated containing a powder mix of the compoundand a suitable powder base such as lactose or starch.

Pharmaceutical compositions of this invention suitable for parenteraladministration comprise one or more compounds of the invention incombination with one or more pharmaceutically acceptable isotonicaqueous or nonaqueous solutions, dispersions, suspensions or emulsions,or powders which may be reconstituted into injectable solutions ordispersions just prior to use, which may contain antioxidants, buffers,bacteriostats, solutes which render the formulation isotonic with theblood of the intended recipient or suspending or thickening agents.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms may be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid, and the like. It may also bedesirable to include isotonic agents, such as sugars, sodium chloride,and the like into the compositions. In addition, prolonged absorption ofthe injectable pharmaceutical form may be brought about by the inclusionof agents which delay absorption such as aluminum monostearate andgelatin.

In some cases, in order to prolong the effect of a drug, it is desirableto slow the absorption of the drug from subcutaneous or intramuscularinjection. This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material having poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionwhich, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally-administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe subject compounds in biodegradable polymers such aspolylactide-polyglycolide. Depending on the ratio of drug to polymer,and the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions which are compatible with body tissue.

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active ingredient which is effective to achieve the desiredtherapeutic response for a particular patient, composition, and mode ofadministration, without being toxic to the patient.

The selected dosage level will depend upon a variety of factorsincluding the activity of the particular compound of the presentinvention employed, or the ester, salt or amide thereof, the route ofadministration, the time of administration, the rate of excretion of theparticular compound being employed, the duration of the treatment, otherdrugs, compounds and/or materials used in combination with theparticular compound employed, the age, sex, weight, condition, generalhealth and prior medical history of the patient being treated, and likefactors well known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the effective amount of the pharmaceuticalcomposition required. For example, the physician or veterinarian couldstart doses of the compounds of the invention employed in thepharmaceutical composition at levels lower than that required in orderto achieve the desired therapeutic effect and gradually increase thedosage until the desired effect is achieved.

In general, a suitable daily dose of a compound of the invention will bethat amount of the compound which is the lowest dose effective toproduce a therapeutic effect. Such an effective dose will generallydepend upon the factors described above. Generally, topical, intravenousand subcutaneous doses of the compounds of this invention for a patient,when used for the indicated effects, will range from about 0.0001 toabout 100 mg per kilogram of body weight per day, more preferably fromabout 0.01 to about 50 mg per kg per day, and still more preferably fromabout 1.0 to about 100 mg per kg per day or preferably from about 1 to500 mg and most preferably from about 1 to 10 mg per kg per day. Eachunit dose may be, for example, 5, 10, 25, 50, 100, 125, 150, 200 or 250mg of a compound according to the invention. If desired, the effectivedaily dose of the active compound may be administered as two, three,four, five, six or more sub-doses administered separately at appropriateintervals throughout the day, optionally, in unit dosage forms.

For use in agricultural applications, the compound or compositions ofthe invention is suspended in an agriculturally acceptable diluent,including but not limited to water or a fertilizer solution. To assurebetter adhesion of the liquid for example, in the case when thesuspension is applied to the plant surface, glycerin can be added to thefinal diluted liquid formulation. The compounds or compositions of theinvention are mixed as a dry ingredient(s) with an inert agriculturallyacceptable particulate dry carrier or diluent which provides a finepowdery formulation. The agriculturally acceptable diluent is one thatserves as a carrier for the low concentrations of compounds orcompositions of the invention. Preferably the dry diluent is one whichreadily suspends in suitable diluents for administration to plants, suchas water.

The formulation is applied to the plant by any of a variety ofart-recognized means. For example, the formulation can be applied to theplant surface by spraying. Alternatively, the solution can be introducedinjectably into a plant, for example, with a syringe, applied as a solidfertilized-like preparation for absorption by the roots at the base of aplant or a solution can be distributed at the base of a plant for rootabsorption. The formulation can be applied as soon as symptoms appear orprophylactically before symptoms appear. Application can be repeated.

Utility

The present invention is the result of the unexpected discovery ofcompounds of Formulas I-III and analogs thereof, inhibit growth,activity and/or the life of microorganisms including parasites,bacteria, algae, protozoa, fungi, viruses or prions, further includingdormant and/or resistant forms such as spores and cysts. Accordingly,compositions containing at least one of the compounds of structuralFormulas I-III inhibit or destroy such microorganisms, and are useful asdisinfectants and as antiseptics, including pharmaceutical agents foranimals, especially mammals, including humans, for the treatment orprevention of diseases. In one embodiment of the invention diseases arethose caused by or associated with infection by microorganismsincluding, but are not limited to, Streptococcus spp., Staphylococcusspp., Clostridium spp., Borrelia spp., Enterococcus spp.Propionibacterium, spp and Peptostreptococcus spp. Haemophilus spp.,Pseudomonas spp., Neisseria spp., Bacillus spp. Yersinia spp.Epidermidis spp., Francisella spp. Coxiella spp., Shigella spp.,Campylobacter spp., Enterococcae spp., E. coli spp., Helicobacter spp.,Klebsiella spp., Moraxella spp., Chlamydia spp., retrovirus,Trichophyton spp., Microsporum spp, Mycobacteria spp. Trichomonas spp,Candida spp, Aspergillus spp. and Coccidioides spp. More preferred areinfections caused by Streptococcus pyogenes, Staphylococcus aureus,methicillin resistant Staphylococcus aureus (“MRSA”), Staphylococcusepidermidis, Neisseria gonorrhoeae, Mycobacteria tuberculosis,vancomycin resistant Enterococcae (“VRE”), Helicobacter pylori, Bacillusanthracis, Chlamydia pneumoniae, Chlamydia trachomatis, HIV,Campylobacter jejuni, Propionibacterium acnes, Pseudomonas aeruginosa,Haemophilus influenzae, Candida albicans, Candida atropicalis,Francisella tularensis, Yersinia pestis, Epidermidis faecalis,Trichophyton rubrum, Trichophyton tonsurans, Trichophytonmentagrophytes, Trichophyton violaceum, Trichophyton cutaneum,Epidermophyton floccosum, Pityrosporum orbiculare, Aspergillusfunigatus, Aspergillus flavus, Aspergillus niger, Coccidioides immitis,Trichomonas hominis, Trichomonas tenax, Trichomonas vaginalis, Giardialamblia, and Toxocara canis.

The present invention is also useful in a method directed to treating orpreventing infections in a host in need of such treatment, which methodcomprises administering a therapeutically effective amount of at leastone of the compounds represented by general Formulas I-III. In oneembodiment, the infected hosts are animals, preferably mammals, mostpreferably human. In another embodiment, the infected host is a plant.

Optionally, nonliving material such as but not limited to soil,surfaces, medical devices etc., may be usefully treated with the instantcompounds to kill microorganisms.

The present invention is also useful in a method of treating orpreventing cancer, central nervous system, cardiovascular, inflammatory,or autoimmune disease in a host in need of such treatment, which methodcomprises administering a therapeutically effective amount of at leastone of compounds represented by general Formulas I-III. In oneembodiment, the hosts are animals, preferably mammals, most preferablyhuman.

The present antimicrobial preparation can also be used in a wide varietyof agriculturally beneficial species such as tobacco, vegetablesincluding cucumber, the Cruciferae, pea and corn, beans such as soybeans, grains including cotton, rice, alfalfa, oat and other cereals,fruits, including apple, pear, peach, plum, tomato, banana, prune andcitrus fruits, tubers and bulbs including potatoes and onions, nutsincluding walnut, grasses including sugar cane and the like.

The antibiotic preparation also is beneficial in the treatment ofnursery plants and ornamental plants such as flowers, includingchrysanthemum, begonia, gladiolus, geranium, carnations and gardenias.

The compositions of the instant invention also find use in the treatmentof shade trees, forest trees, annual field crops and biannual fieldcrops.

Other plant species in which the compositions of the invention can beused are Espinas, Cotoneaster, Phyrachanthas, Stranvaesis, Fraxinus,Pyrus, Malus, Capsicum, Cydonia, Crataegus and Soreus.

Besides their use as medicaments in human, veterinary or plant therapy,the compounds of the invention can also be used as animal growthpromoters. For this purpose, a compound of the invention is administeredorally in a suitable feed. The exact concentration employed is thatwhich is required to provide for the active agent in a growth promotanteffective amount when normal amounts of feed are consumed.

The addition of the active compound of the invention to animal feed ispreferably accomplished by preparing an appropriate feed premixcontaining the active compound in an effective amount and incorporatingthe premix into the complete ration. Alternatively, an intermediateconcentrate or feed supplement containing the active ingredient can beblended into the feed. The way in which such feed premixes and completerations can be prepared and administered are described in referencebooks (such as such as “Applied Animal Nutrition”, W.H. Freedman andCO., S. Francisco, USA, 1969 or “Livestock Feeds and Feeding” O and Bbooks, Corvallis, Oreg., USA, 1977), incorporated herein in itsentirety.

Nonliving material such as but not limited to soil, porous andnon-porous surfaces, etc., may be usefully treated with the instantcompounds and compositions comprising the compounds to remove, retard orreduce the growth or, infectivity of parasites, bacteria, algae, fungi,viruses or prions including dormant and/or resistant forms such asspores and cysts, and disinfect the surface. The disinfectantcompositions may be applied for example in a spray, foam or dip.

EXAMPLES Example 11,1-Bis(4-hydroxy-3-methylphenyl)-3-n-propyl-cyclobutane

To a stirred mixture of 3-n-propyl-cyclobutanone (200 mg, 1.783 mmol),O-cresol (386 mg, 3.570 mmol) and water (0.16 ml) was added 95% sulfuricacid (0.65 g). The mixture was stirred at room temperature overnight.Water (10 ml) was added and the mixture was extracted with ethyl acetate(10 ml×3). The organic layer was washed with water, dried over anhydroussodium sulfate, filtered and evaporated. The crude residue was purifiedby flash chromatography on SiO₂ column eluted with ethyl acetate/hexane(30%). The final product (145 mg, 26%) was obtained as white powder.

-   Mp: 130-132° C.;-   C₂₁H₂₆O₂ (310.1933): MS (EI+) m/e: 310;-   HRMS (EI+)m/e: 310.1937.-   This product was also analyzed by ¹H and ¹³C NMR. The corresponding    NMR spectra were consistent with the structure of the anticipated    product.

Example 2 1,1-Bis(4-hydroxy-3-methylphenyl)-3-n-butyl-cyclobutane

To a stirred mixture of 3-butyl-n-cyclobutanone (7.26 g, 57.5 mmol),O-cresol (12.44 g, 115 mmol) and water (5.2 ml) was added 95% sulfuricacid (2.80 g) at 0° C. The mixture was stirred at room temperatureovernight. Water (200 ml) was added and the mixture was extracted withether (150 ml×2). The ether layer was washed with water, dried overanhydrous sodium sulfate, filtered and evaporated. The crude solidresidue was washed with cold hexane (30 ml×3). The final product (13.54g, 73%) was obtained as white powder.

-   Mp: 135-137° C.;-   C₂₁H₂₆O₂ (324.2089):-   MS (EI+)m/e: 324;-   HRMS (EI+) m/e: 324.2087.-   This product was also analyzed by ¹H and ¹³C NMR. The corresponding    NMR spectra were consistent with the structure of the anticipated    product.

Example 3 1,1-Bis(4-hydroxyphenyl)-3-n-propyl-cyclobutane

To a stirred mixture of 3-n-propyl-cyclobutanone (400 mg, 3.57 mmol),phenol (671 mg, 7.132 mmol) and water (0.32 ml) was added 95% sulfuricacid (1.30 g). The mixture was stirred at room temperature overnight.Water (10 ml) was added and the mixture was extracted with ethyl acetate(10 ml×3). The organic layer was washed with water, dried over anhydroussodium sulfate, filtered and evaporated. The crude residue was purifiedby flash chromatography on SiO₂ column eluted with ethyl acetate/hexane(30%). The final product (326 mg, 32%) was obtained as gum.

-   C₁₉H₂₂O₂ (282.1620):-   MS (EI+) m/e: 282;-   HRMS (EI+) m/e: 282.1611.-   This product was also analyzed by ¹H and ¹³C NMR. The corresponding    NMR spectra were consistent with the structure of the anticipated    product.

Example 41-(4-Hydroxyphenyl)-1-(4-hydroxy-3-chloro-phenyl)-3-n-propyl-cyclobutaneand Example 5 1,1-Bis(4-hydroxy-3-chloro-phenyl)-3-n-propyl-cyclobutane

To a solution of 1,1-bis(4-hydroxyphenyl)-3-n-propyl-cyclobutane (200mg, 0.708 mmol), and diisopropylamine (8 μl, 8 mol %) in toluene (2 ml)at 70° C. was added sulfuryl chloride (85 μl) dropwise. After beingstirred at 70° C. for 30 minutes, the reaction mixture was poured intowater (20 ml) and extracted with ether (10 ml×2). The organic layer waswashed with water, dried over anhydrous sodium sulfate, filtered andevaporated. The residue was purified by flash chromatography on SiO₂column eluted with gradient of ethyl acetate/hexane from 15% to 30%. Thefinal products were obtained as white powders.

1-(4-Hydroxyphenyl)-1-(4-hydroxy-3-chloro-phenyl)-3-propylcyclobutane(80 mg, 25%):

-   Mp: 104-108° C.;-   C₁₉H₂₁ClO₂ (316.1230):-   MS (EI+) m/e: 316;-   HRMS (EI+) m/e: 316.1224;    1,1-Bis(4-hydroxy-3-chloro-phenyl)-3-propyl-cyclobutane (42 mg,    12%),-   Mp: 103-105° C.;-   C₁₉H₂₀Cl₂O₂ (350.0840):-   MS (EI+) m/e 350.-   HRMS (EI+) m/e: 350.0838.-   The products were also analyzed by ¹H and ¹³C NMR. The corresponding    NMR spectra were consistent with the structure of the anticipated    product.

Example 6 1,1-Bis(4-hydroxyphenyl)-3-n-butyl-cyclobutane

To a stirred mixture of 3-n-butyl-cyclobutanone (550 mg, 4.36 mmol),phenol (820 mg, 8.72 mmol) and water (0.4 ml) was added 95% sulfuricacid (1.59 g). The mixture was stirred at room temperature overnight.Water (10 ml) was added and the mixture was extracted withdichloromethane (10 ml×3). The organic layer was washed with water,dried over anhydrous sodium sulfate, filtered and evaporated. The cruderesidue was purified by flash chromatography on SiO₂ column eluted withethyl acetate/hexane (30%). The final product (326 mg, 32%) was obtainedas white powder.

-   C₂₀H₂₄O₂ (296.1776):-   MS (EI+) m/e: 296;-   HRMS (EI+) m/e: 296.1782.-   This product was also analyzed by ¹H and ¹³C NMR. The corresponding    NMR spectra were consistent with the structure of the anticipated    product.

Example 71-(4-Hydroxyphenyl)-1-(4-hydroxy-3-chlorophenyl)-3-n-butyl-cyclobutaneand Example 8 1,1-Bis(4-hydroxy-3-chloro-phenyl)-3-n-butyl-yclobutane

To a solution of 1,1-bis(4-hydroxyphenyl)-3-butyl-cyclobutane (300 mg,1.012 mmol), and diisopropylamine (11 μl, 8 mol %) in toluene (3 ml) at70° C. was added sulfuryl chloride (100 μl) dropwise. After beingstirred at 70° C. for 30 minutes, the reaction mixture was quenched withwater (20 ml) and extracted with ether (15 ml×2). The organic layer waswashed with water, dried over anhydrous sodium sulfate, filtered andevaporated. The residue was purified by flash chromatography on SiO₂column eluted with gradient of ethyl acetate/hexane from 15% to 30%. Thefinal products were obtained as white powders.

1-(4-Hydroxyphenyl)-1-(4-hydroxy-3-chloro-phenyl)-3-butylcyclobutane(120 mg, 36%).

-   Mp: 104-105° C.;-   C₂₀H₂₃ClO₂ (330.1387):-   MS (EI+)m/e: 330;-   HRMS (EI+)m/e: 330.1381;    1,1-Bis(4-hydroxy-3-chloro-phenyl)-3-propyl-cyclobutane (67 mg,    18%):-   Mp: 90-92° C.;-   C₂₀H₂₂Cl₂O₂ (364.0997):-   MS (EI+) m/e 364;-   HRMS (EI+) M/e: 364.0997.-   The products were also analyzed by ¹H and ¹³C NMR, The corresponding    NMR spectra were consistent with the structure of the anticipated    product.

Example 9 2,2-Bis(4-hydroxy-3-methylphenyl)heptane

To a mixture of O-cresol (20.00 g, 0.185 mol), 2-heptanone (10.56 g,0.0925 mol) and water (8 ml) was added dropwise 95% sulfuric acid (34g). After being stirred for 18 hours at room temperature, the mixturewas diluted with water (200 ml) and extracted with ether (100 ml×3). Theethereal phase was washed with water, dried over anhydrous sodiumsulfate, filtered and evaporated. The above procedure was repeated andthe combined residue was purified by flash chromatography on silicacolumn eluted with gradient of ethyl acetate/hexane (15%-30%). Thecollected fraction was concentrated and the residue was mixed withhexane (50 ml) and a seed of crystal of2,2-Bis(4-hydroxy-3-methylphenyl)heptane and cooled overnight. The solidwas collected by filtration, washed with cold hexane and dried invacuum. The final product (17.90 g, 62%) was obtained as white powder.

-   Mp: 99-101° C.-   C₂₁H₂₈O₂ (312.43):-   MS (EI+) m/e: 312;

Elemental Analysis: Calcd, C: 80.73%, H: 9.19%; found, C: 80.73%, H:9.19.

The product was also analyzed by ¹H-NMR and ¹³C-NMR. The analytic andspectra data confirm the product is the one reported as Compound 5 inDomagala et al. In Resolving the Antibiotic Paradox, ed by Rosen andMabashery, page 269, 1998.

Example 10 1,1-Bis(4-hydroxy-3-methylphenyl)-2-n-butylcyclopropane

First step: 1,1-bis(4-methoxy-3-methylphenyl)-1-hexene

An oven-dried flask, equipped with condenser, dropping funnel, argoninlet and outlet was charged with magnesium powder (1.50 g, 61.70 mmol)and THF (6 mL) and purged with argon for 5 minutes. 3 mL of the solutionmade from 4-bromo-3-methylanisole (10.0 g, 49.73 mmol) and THF (8 mL)was added. When the reaction mixture started to reflux, the rest of thebromide solution was added dropwise to maintain refluxing. After theaddition was completed, the mixture was heated to reflux for anotherhour and cooled down to room temperature. To this was added a solutionof ethyl caproate in THF (10 mL) dropwise. After being stirred atambient temperature overnight. The reaction mixture was quenched withice and saturated ammonium chloride solution and extracted with ether(2×50 mL). The combined organic layer was washed with water (2×20 mL),dried over Na₂SO₄, filtered and evaporated. The residue was thenpurified by column chromatography on silica column eluted with gradientof ethyl acetate/hexane from 15% to 30%. The title compound (3.135 g,39%) was obtained as colorless oil.

-   C₂₂H₂₈O₂ (324.2089):-   MS (EI) m/e 324;-   HRMS (EI) m/e 324.2079.-   This product was also analyzed by ¹H and ¹³C NMR. The corresponding    NMR spectra were consistent with the structure of the anticipated    product.    Second step: 1,1-bis(4-methoxy-3-methylphenyl)-2-n-butylcyclopropane

A oven-dried flask, equipped with argon purging system and septa wascharged with a solution of 1,1-bis(4-hydroxy-3-methylphenyl)-1-hexene(1.50 g, 4.62 mmol) in toluene (10 mL), and heated at 60° C. 1.0 Mdiethyl zinc solution in hexane (9.4 mL, 9.4 mmol) and subsequentlydiiodomethane (0.744 mL, 9.4 mmol) was added dropwise by syringe. Thesame operation was repeated twice in 24 hours interval (totally, 9.4mL×3, 28.2 mmol of diethyl zinc and 0.744 mL×3, 28.2 mmol ofdiiodomethane added). After being stirred at 60° C. for five days, thereaction mixture was quenched with 0.5 N hydrochloric acid, extractedwith ether (50 mL×3). The combined organic layer was washed with water,dried over Na₂SO₄, filtered and evaporated. The title compound wasobtained as colorless oil (1.56 g, 99%), which was used for step withoutfurther purification.

-   C₂₃H₃₀O₂ (338.2246):-   MS (EI) m/e 338 (M⁺);-   HRMS (EI) m/e 338.2252.-   This product was also analyzed by ¹H and ¹³C NMR. The corresponding    NMR spectra were consistent with the structure of the anticipated    product.    The third step:    1,1-bis(4-hydroxy-3-methylphenyl)-2-n-butylcyclopropane

To a stirred solution of1,1-bis(4-methoxy-3-methylphenyl)-2-n-butylcyclopropane (0.80 g, 2.36mmol) in dichloromethane (10 mL) was added boron tribromide (0.22 mL,2.36 mmol) at room temperature. After being stirred overnight, thedeep-colored solution was quenched with water, extracted withdichloromethane (3×10 mL). The organic layer was washed with saturatedaqueous NaHCO₃ and water, dried over Na₂SO₄, filtered and evaporated.The crude residue was purified twice by flash chromatography on silicacolumn eluted with ethyl acetate/hexane (15%), giving the title compound(205 mg, 28%) as yellowish gum.

-   C₂₁H₂₆O₂ (310.1921):-   MS (EI) m/e 310 (M⁺);-   HRMS (EI) m/e 310.1933.-   This product was also analyzed by ¹H and ¹³C NMR. The corresponding    NMR spectra were consistent with the structure of the anticipated    product.

Example 11 1,1-Di(4-hydroxyphenyl)-3-(2,2-dimethylpropyl)cyclobutane

First step: 3-(2,2-dimethyl-propyl)cyclobutanone

To a solution of N,N-dimethylacetamide (8.7 g, 100 mmol) in methylenechloride (300 mL) at −16° C. under argon triflic anhydride (33.8 g, 120mmol) was added slowly over 5 minutes through a syringe. Yellowprecipitate formed immediately and the stirring was continued at −16° C.for 30 min. A mixture of 4,4-dimethyl-1-pentene (10.0 g, 101.8 mmol) andcollidine (14.6 g, 120 mmol) was added slowly over 5 min. The mixturewas then allowed to gradually warm up to room temperature andsubsequently refluxed for 28 hours. After solvents were removed byreduced pressure, the resultant black residue was washed with dry ether(2×40 mL), and mixed with H₂O (100 mL) and pentane (300 mL). The mixturewas then stirred for 20 hours. The organic layer was separated and theaqueous layer was extracted with pentane (50 mL). The combined pentanelayer was washed with 30 ml of water and dried over Na₂SO₄, Afterremoval of pentane by fractional distillation, yellowish liquid (5.5 g,40%) was obtained as the product.

The second step:1,1-di(4-hydroxyphenyl)-3-(2,2-dimethylpropyl)cyclobutane

To a stirred mixture of 3-(2,2-dimethylpropyl) cyclobutanone (300 mg,2.1 mmol) and phenol (470 mg, 5.0 mmol) was added 75% sulfuric acid (0.5mL). The mixture was stirred at room temperature overnight. Na₂CO₃ wasadded and the mixture was loaded on silica gel. The crude residue waspurified by flash chromatography on SiO₂ column eluted with ethylether/hexane (10% to 20%). The final product (30 mg, 4.5%) was obtainedas white powder.

-   Mp: 182-184° C.-   C₂₁H₂₆O₂ (310.1933):-   MS (EI) m/e 310 (M⁺);-   HRMS (EI) m/e 310.1933.-   This product was also analyzed by ¹H and ¹³C NMR. The corresponding    NMR spectra were consistent with the structure of the anticipated    product.

Example 121,1-Di(4-hydroxy-3-methylphenyl)-3-(2,2-dimethylpropyl)cyclobutane

Using methods of the second step in Example 11, the reaction of3-(2,2-dimethyl-propyl)cyclobutanone (4.60 mg, 32.85 mmol), O-cresol(12.9 g, 119.4 mmol) in the presence of 75% sulfuric acid (12.0 mL) gavethe title compound (2.50 g, 4.5%) as white powder.

-   Mp: 175-176° C.-   C₂₃H₃₀O₂ (338.2246):-   MS (EI) m/e 338 (M⁺);-   HRMS (EI) m/e 338.2243.-   This product was also analyzed by ¹H and ¹³C-NMR. The corresponding    NMR spectra were consistent with the structure of the anticipated    product.

Example 13Trans-1,1-di(4-hydroxyphenyl)-3-(2,2-dimethylpropyl)-2-methylcyclobutaneand Example 14Cis-1,1-di(4-hydroxyphenyl)-3-(2,2-dimethylpropyl)-2-methylcyclobutane

Using methods of the second step in Example 11, the reaction of2-methyl-3-neopentylcyclobutanone (1.0 g, 6.49 mmol) and phenol (3.30 g,31.9 mmol) in the presence of 75% sulfuric acid (2.0 g) afforded trans(530 mg, 25.2%) and cis (50 mg, 2.4%) isomers of the title compound aswhite powders.

-   For the trans isomer: mp: 154-156° C.-   For the cis isomer, mp: 79-81° C.-   C₂₂H₂₈O₂ (324.2091):-   MS (EI) m/e 324 (M⁺);-   HRMS (EI) m/e 324.2089.-   These products was also analyzed by ¹H and ¹³C NMR. The    corresponding NMR spectra were consistent with the structure of the    anticipated product.

Example 15Trans-1,1-di-(4-hydroxy-3-methylphenyl)-3-(2,2-dimethylpropyl)-2-methylcyclobutane

Using methods of the second step in Example 11, the reaction of2-methyl-3-neopentylcyclobutanone (1.0 g, 6.49 mmol) and O-cresol (3.80g, 35.18 mmol) in the presence of 75% sulfuric acid (2.0 g) gave thefinal product (500 mg, 24.9%) as white powder.

-   Mp: 160-162° C.-   C₂₃H₃₀O₂ (338.2246):-   MS (EI) m/e 338 (M⁺);-   HRMS (EI) m/e 338.2243.-   This product was also analyzed by ¹H and ¹³C NMR. The corresponding    NMR spectra were consistent with the structure of the anticipated    product.

Example 161,1-Di-(4-hydroxy-3-methylphenyl)-3-(1,1-dimethylethyl)cyclobutane

Using methods of the second step in Example 11, the reaction of3-tert-butylcyclobutanone (360 mg, 6.49 mmol) and O-cresol (2.3 g, 21.3mmol) in the presence of 75% sulfuric acid (1.0 g) gave the titlecompound (110 mg, 11.8%) as white powder.

-   Mp: 185-187° C.-   This product was also analyzed by ¹H and ¹³C NMR. The corresponding    NMR spectra were consistent with the structure of the anticipated    product.

Example 17 1,1-Di-(4-hydroxyphenyl)-3-(1,1-dimethylethyl)cyclobutane

Using methods of the second step in Example 11, the reaction of3-tert-butylcyclobutanone (485 mg, 3.85 mmol) and O-cresol (2.0 g, 18.5mmol) in the presence of 75% sulfuric acid (1.3 g) gave the titlecompound (300 mg, 26.3%) as white powder.

-   Mp: 187-189° C.-   This product was also analyzed by ¹H and ¹³C NMR. The corresponding    NMR spectra were consistent with the structure of the anticipated    product.

Example 18 The first step: 1,1-di(4-methoxyphenyl)-1-hexene

A solution of ethyl caproate (4.38 g, 30 mmol) in 10 mL of anhydrousethyl ether was placed in a three-necked round-bottomed flask equippedwith a stopper, a condenser and a septum. Methoxyphenylmagnesium bromidein THF (0.5 M, 300 mL, 150 mmol) was added slowly through syringe andthe reaction mixture was stirred overnight under argon at ambienttemperature. After being quenched with ice-water (50 mL), the aqueouslayer was separated and extracted with ether (2×50 mL). The combinedorganic layer was washed with H₂O (2×20 mL), dried over Na₂SO₄ andevaporated in vacuo to give yellow oil, which was distilled to afford8.2 g (92%) of colorless oil. Further purification by columnchromatography (SiO₂, 250 g) eluted with hexane/ether (4/1) afforded 7.3g. of colorless oil as the final product.

-   Bp: 195° C. (0.7 mm Hg)

The second step: 1,1-di(4-methoxyphenyl)-2-n-butylcyclopropane

A solution of 1,1-di(4-methoxyphenyl)-1-hexene (2.96 g, 10 mmol) in 20mL of toluene was placed in a round-bottomed flask equipped with astirring bar and a septum. Diethyl zinc (1.0 M, 80 mL, 80 mmol) wasadded and the mixture was heated to 60° C. under argon. Diiodomethane(7.0 mL, 87.6 mmol) was added slowly through syringe pump at thistemperature over 2 hours. The stirring was continued at 60° C. underargon for 8 days. Water (3.0 mL) was added followed by hexane (100 mL)and ether (100 mL). The mixture was filtered through celite. Thesolvents were removed by evaporating under reduced pressure. Theresidual was taken up into hexane (3×50 mL), which afforded yellow oil(3.2 g) after removal of hexane.

To a cooled solution (0° C.) of the residue in CHCl₃ (4 mL) was addedm-CPBA (0.6 g) in portions. The mixture was gradually warmed up to roomtemperature and stirred for 30 min. Na₂CO₃ was added and the mixture wasstirred at room temperature for another 30 min. The solvent was removedand the residual was loaded onto SiO₂ (10 g). Purification by columnchromatography (SiO₂, 300 g) eluted with hexane/ether (9/1) afforded theproduct (2.1 g) as pale yellow oil.

-   MS (C₂₁H₂₆O₂) : (EI) m/e 310 (M⁺),

The third step: 1,1-Di(4-hydroxyphenyl)-2-n-butylcyclopropane

A solution of 1,1-di(4-methoxyphenyl)-2-n-butylcyclopropane (930 mg, 3.0mmol) in of methylene chloride (30 mL) was placed in a round-bottomedflask equipped with a stirring bar and a septum. The mixture was cooledto −78° C. under argon. BBr₃ (0.70 mL, 7.0 mmol) was added dropwisethrough syringe at this temperature. The reaction mixture was stirred at−78° C. for 130 min and was then allowed to warm up to room temperature.The dark mixture was quenched with water (3.0 mL) and stirred for 20min. The aqueous layer was separated and extracted with methylenechloride (15 mL). The organic layer was combined, washed with water.After the solvent was removed by evaporating under reduced pressure, theblack residual was loaded onto SiO₂ (5 g) and purified by chromatographyon SiO₂ (30 g) column eluted with ether/hexane (1/4). The title compound(430 mg, 65%) was obtained as a greenish solid.

-   C₁₉H₂₂O₂ (282.1620):-   MS (EI) m/e 282 (M⁺);-   HRMS (EI) m/e 282.1615.-   This product was also analyzed by ¹H and ¹³C NMR. The corresponding    NMR spectra were consistent with the structure of the anticipated    product.

Example 19 1,1-Di(4-hydroxyphenyl)-2-n-pentylcyclopropane

Using methods of Example 18, demethylation of1,1-di(4-methoxyphenyl)-2-n-pentylcyclopropane (1.04 g, 3.21 mmol) withboron tribromide (0.65 mL, 6.89 mmol) in methylene chloride gave thefinal product (0.43 g, 45%) as greenish powder.

-   C₂₀H₂₄O₂ (296.1776):-   MS (EI) m/e 296 (M⁺);-   HRMS (EI) m/e 296.1774.-   This product was also analyzed by ¹H and ¹³C NMR. The corresponding    NMR spectra were consistent with the structure of the anticipated    product.

Examples 20 1,1-Di(3-chloro-4-hydroxyphenyl)-2-n-butylcyclopropane; andExample 211-(3-Chloro-4-hydroxyphenyl)-1-(4-hydroxy-3,5-dichlorophenyl)-2-n-butylcyclopropane

A solution of 1,1-di(4-hydroxyphenyl)-2-n-butylcyclopropane (110 mg,0.39 mmol), and diisopropyl amine (5 μL, 0.036 mmol) in 10 mL of toluenewas placed in a round-bottomed flask equipped with a stirring bar and aseptum. The mixture was heated to 70° C. under argon while sulfurylchloride (50 μL, 0.61 mmol) was added slowly through syringe over 10min. After being stirred at 70° C. for 30 min, the solvent was removedand the residual was loaded onto SiO₂ (1 g). Purification by columnchromatography (SiO₂, 30 g) eluted with hexane/ether (85/15→80/20)afforded 1,1-di(3-chloro-4-hydroxyphenyl)-2-n-butyl-cyclopropane (30 mg,22%) as a pale brown grease and1-(3-chloro-4-hydroxyphenyl)-1-(4-hydroxy-3,5-dichloro-phenyl)-2-n-butyl-cyclopropane(12 mg, 9.7%).

For 1,1-di(3-chloro-4-hydroxyphenyl)-2-n-butyl-cyclopropane,

-   C₁₉H₂C₁₂O₂ (350.0840):-   MS (EI) m/e 352 (M⁺);-   HRMS (EI) m/e 350.0839.-   These products were also analyzed by ¹H and ¹³C NMR. The    corresponding NMR spectra were consistent with the structure of the    anticipated product.

Example 22 1,1-Di(3-chloro-4-hydroxyphenyl)-2-pentylcyclopropane andExample 231-(3-Chloro-4-hydroxyphenyl)-1-(4-hydroxy-3,5-dichlorophenyl)-2-pentylcyclopropane

Using methods of Example 20,1,1-di-4′-hydroxyphenyl-2-n-pentylcyclopropane (113 mg, 0.381 mmol) waschlorinated with sulfuryl chloride (63 μL, 0.78 mmol) to give1,1-di(3-chloro-4-hydroxyphenyl)-2-pentylcyclopropane (65 mg, 46.7%) and1-(3-chloro-4-hydroxyphenyl)-1-(4-hydroxy-3,5-dichlorophenyl)-2-pentylcyclopropane(15 mg, 12%) as greenish greases.

For 1,1-di(3-chloro-4-hydroxyphenyl)-2-pentylcyclopropane,

-   MS (C₂₀H₂₂Cl₂O₂) (EI) m/e 364 (M⁺)    For    1-(3-chloro-4-hydroxyphenyl)-1-(4-hydroxy-3,5-dichlorophenyl)-2-pentylcyclopropane,-   MS (C₂₀H₂₁Cl₃O₂) (EI) m/e 398 (M⁺)-   These product was also analyzed by ¹H and ¹³C NMR. The corresponding    NMR spectra were consistent with the structure of the anticipated    product.

Example 241,1-Di-(3-chloro-4-hydroxyphenyl)-3-(2,2-dimethylpropyl)cyclobutane

Using methods of Example 20,1,1-di-(4-hydroxyphenyl)-3-(2,2-dimethylpropyl)cyclobutane (24 mg, 0.071mmol) was chlorinated with sulfuryl chloride (21.6 mg, 0.16 mmol) togive 1,1-di(3-chloro-4-hydroxyphenyl)-3-(2,2-dimethylpropyl)cyclobutane(8 mg, 27%) as light brown solid.

-   Mp: 131-134° C.-   C₂₁H₂₄Cl₂O₂ (378.1153):-   MS (EI) m/e 378 (M⁺),-   HRMS (EI) m/e 378.1142.-   This product was also analyzed by ¹H and ¹³C NMR. The corresponding    NMR spectra were consistent with the structure of the anticipated    product.

Example 251,1-Di-(3-chloro-4-hydroxyphenyl)-2-(1,1-dimethylethyl)cyclobutane

Using methods of Example 20,1,1-di-(4-hydroxyphenyl)-3-(1,1-dimethyl-ethylyl)cyclobutane (186 mg,0.63 mmol) was chlorinated with sulfuryl chloride (178 mg, 1.32 mmol) togive the title compound (40 mg, 17%) as white powder.

-   Mp: 133-135° C.-   MS (C₂₀H₂₂Cl₂O₂): (EI) m/e 364 (M⁺)-   This product was also analyzed by ¹H and ¹³C NMR. The corresponding    NMR spectra were consistent with the structure of the anticipated    product.

Example 26Trans-1,1-Di(3-chloro-4-hydroxyphenyl)-3-(2,2-dimethylpropyl)-2-methylcyclobutane

Using methods of Example 20,1,1-Di(4-hydroxyphenyl)-3-(2,2-dimethylpropyl)-2-methylcyclobutane (186mg, 0.63 mmol) was chlorinated with sulfuryl chloride (178 mg, 1.32mmol) to give title compound (40 mg, 17%) as white powder.

-   Mp: 126-128° C.-   C₂₂H₂₆Cl₂O₂ (392.1310):-   MS (EI) m/e 392 (M⁺),-   HRMS (EI) m/e 392.1301.-   This product was also analyzed by ¹H and ¹³C NMR. The corresponding    NMR spectra were consistent with the structure of the anticipated    product.

Examples 27Trans-1,1-di(5-chloro-4-hydroxy-3-methylphenyl)-3-(2,2-dimethylpropyl)-2-methylcyclobutaneand Example 28Trans-1-(4-hydroxy-3-methylphenyl)-1-(5-chloro-4-hydroxy-3-methylphenyl)-3-(2,2-dimethylpropyl)-2-methylcyclobutane

Using methods of Example 20,trans-1,1-di(4-hydroxy-3-methylphenyl)-3-(2,2-dimethylpropyl)-2-methylcyclobutane(245 mg, 0.63 mmol) was chlorinated with sulfuryl chloride (170 mg, 1.32mmol) to givetrans-l,1-di(5-chloro-4-hydroxy-3-methylphenyl)-3-(2,2-dimethylpropyl)-2-methylcyclobutane(50 mg, 17%) andtrans-1-(4-hydroxy-3-methylphenyl)-1-(5-chloro-4-hydroxy-3-methylphenyl)-3-(2,2-dimethylpropyl)-2-methylcyclobutane(90 mg, 33%) as white powder.

Fortrans-1,l-Di(5-chloro-4-hydroxy-3-methylphenyl)-3-(2,2-dimethylpropyl)-2-methylcyclobutan:

-   mp: 131-133° C.-   C₂₄H₃₀Cl₂O₂ (420.1623):-   MS (EI) m/e 421 (M⁺),-   HRMS (EI) m/e 420.1622.    For    Trans-1-(4-hydroxy-3-methylphenyl)-1-(5-chloro-4-hydroxy-3-methylphenyl)-3-(2,2-dimethylpropyl)-2-methylcyclobutane:-   mp: 138-140° C.-   C₂₂H₃₁ClO₂ (386.2013):-   MS (EI) m/e 386 (M⁺),-   HRMS (EI) m/e 386.2013.-   These products were also analyzed by ¹H and ¹³C NMR. The    corresponding NMR spectra were consistent with the structure of the    anticipated product.

Example 29 1,1-Di(3-ethyl-4-hydroxyphenyl)-3-n-butylcyclobutane

Using the methods of Example 12, the reaction of 3-n-butylcyclobutanone(500 mg, 3.96 mmol) and ethylphenol (0.933 g, 7.92 mmol) in the presenceof 75% sulfuric acid (2.0 g) gave the title compound (298 mg, 21%) aslight pink powder.

-   Mp: 135-138° C.-   C₂₄H₃₂O₂ (352.52): MS (EI) m/e 352 (M⁺)-   This product was also analyzed by ¹H and 13C NMR. The corresponding    NMR spectra were consistent with the structure of the anticipated    product.)

Example 30 1,1-Di(3,5-dimethyl-4-hydroxyphenyl)-3-n-butylcyclobutane

-   Using the methods of Example 12, the reaction of    3-n-butylcyclobutanone (500 mg, 3.96 mmol) and 2,6-dimethylphenol    (0.958 g, 7.92 mmol) in the presence of 75% sulfuric acid (2.0 g)    gave the title compound (200 mg, 14%) as an off-white powder.-   Mp: 138-141° C.-   C₂₄H₃₂O₂ (352.52): MS (EI) m/e 352 (M⁺)-   This product was also analyzed by ¹H and ¹³C NMR. The corresponding    NMR spectra were consistent with the structure of the anticipated    product.

Example 31 1,1-Di(3-ethyl-4-hydroxyphenyl)-3-n-pentylcyclobutane

Using the methods of Example 12, the reaction of 3-n-pentylcyclobutanone(500 mg, 3.57 mmol) and 2-ethylphenol (871 mg, 7.13 mmol) in thepresence of 75% sulfuric acid (1.7 g) gave the title compound (490 mg,37%) as white powder.

-   Mp: 109-111° C.-   C₂₅H₃₄O₂ (366.2559): MS (EI) m/e 366 (M⁺), HRMS (EI) m/e 366.2544.-   This product was also analyzed by ¹H and ¹³C NMR. The corresponding    NMR spectra were consistent with the structure of the anticipated    product.

Example 32 1,1-Di(3,5-dimethyl-4-hydroxyphenyl)-3-n-pentylcyclobutane

Using the methods of Example 12, the reaction of 3-n-pentylcyclobutanone(500 mg, 3.57 mmol) and 2,6-dimethylphenol (871 mg, 7.13 mmol) in thepresence of 75% sulfuric acid (1.7 g) gave the title compound (243 mg,26.3%) as white powder.

-   Mp: 115-117° C.-   C₂₅H₃₄O₂ (366.2559): MS (EI) m/e 366 (M⁺), HRMS (EI) m/e 366.2554.-   This product was also analyzed by ¹H and ¹³C NMR. The corresponding    NMR spectra were consistent with the structure of the anticipated    product.

Example 33 1,1-Di(3-allyl-4-hydroxyphenyl)-3-n-butylcyclobutane

To a solution of 3-n-butyl-1,1-di(4-hydroxyphenyl)cyclobutane (590 mg,2.0 mmol) in CH₃CN (10 mL) was added KOH (240 mg, 4.0 mmol) followed by18-crown-6 (20 mg) at ambient temperature. The mixture was stirred atambient temperature for 20 min, before allyl bromide (1.0 g, 8.2 mmol)was added. After the reaction mixture was stirred at ambient temperatureovernight, hexane (30 ml) was added and the mixture was passed through ashort column followed by rinsing with (ether/hexane (1/9), 10 mL). Afterremoval of solvents, 1,1-di(4-allyloxyphenyl)-3-n-butylcyclobutane (710mg) was obtained as colorless oil.

The above oil (500 mg) was dissolved in ethylene glycol (10.0 mL) andwas stirred at 170° C. for 6.5 h under Argon. The reaction was cooled toambient temperature and water (30 mL) and ether (30 mL) was added. Theaqueous layer was separated and the solvents were removed. The resultantresidual was separated by flash chromatography (SiO₂, ether/hexane,1/3). Amorphous solid (50 mg, 10%) was obtained as product.

-   C₁₈H₂₀O₂ (376.53): MS (EI) m/e 376 (M⁺),-   This product was also analyzed by ¹H and ¹³C NMR. The corresponding    NMR spectra were consistent with the structure of the anticipated    product.

Example 34 Synthesis of 9-Pentyl-9H-fluorene-3, 6-diol

To a cold (−10° C.) solution of 3,3′-dimethoxy biphenyl (8.0 g, 37.3mmol) in DMF (24 mL), was added a solution of NBS (13.2 g, 74.2 mmol) inDMF (55 mL) over 1 hr. The reaction mixture was allowed to warm up toambient temperature, stirred for 24 hours and then poured into ice-water(100 mL). The white solid was collected, dissolved in CH₂Cl₂ (100 mL),washed with water and mixed with hexane (200 mL). The DCM was slowlyremoved by heating on water bath. 2,2′-Dibromo-5,5′dimethoxy-biphenylwas obtained as needle crystal (9.9 g) after filtration and drying in avacuum at ambient temperature overnight.

To a cold (−18° C.) solution of 2,2′-Dibromo-5,5′dimethoxy-biphenyl (372mg, 1.0 mmol) in THF (10 mL), was added butyllithium (2.5 M/pentane, 1.0mL, 2.5 mmol) over 10 min. The reaction mixture was stirred at thattemperature for 30 min before it was allowed to warm up to roomtemperature. The mixture was stirred for 5 min and was cooled to −18° C.again. Ethyl caproate (144 mg, 1.0 mmol) was added and the reactionmixture was allowed to warm up to ambient temperature gradually andstirred overnight. The reaction was quenched with HCl (1.0 N, 5.0 mL)and extracted with ether (50 mL). The organic layer was washed withwater (10 mL) and evaporated. The residual was passed a short SiO₂column followed by rinsing with hexane and hexane/ether (1/1).3,6-Dimethoxy-9-pentyl-9H-fluoren-9-ol was obtained as off white solid(196 mg).

To a 3,6-dimethoxy-9-pentyl-9H-fluoren-9-ol (152 mg) solution inmethylene chloride (5 mL), was added triethylsilane (200 mg) followed bytrifluoroacetic acid (0.2 mL) at ambient temperature. The reactionmixture was stirred at ambient temperature for 1 hr and then evaporated.The residual was purified by flash chromatography (SiO₂, 6 g,pentane/ether, 9/1). 3,6-Dimethoxy-9-n-pentyl-9H-fluorene (105 mg) wasobtained as yellowish oil.

To a cold (−75° C.) solution of 3,6-dimethoxy-9-n-pentyl-9H fluorene (33mg, 0.11 mmol) in methylene chloride (2 mL), was added boron tribromide(50 mg) dropwise. The reaction mixture was stirred at that temperaturefor 30 min and allowed to warm up to ambient temperature and stirred foranother 30 min. The reaction mixture was quenched with water (10 mL),extracted with ether (30 mL) separated and concentrated. The residualwas loaded onto SiO₂ (21.0 g). Column chromatography purification (SiO₂,pentane/ether, 1:1) gave 9-n-pentyl-9H-fluorene-3,6-diol as a yellowsolid (18 mg).

-   C₁₈H₂₀O₂ (268.35): MS (EI) m/e 268 (M⁺),-   This product was also analyzed by ¹H and ¹³C NMR. The corresponding    NMR spectra were consistent with the structure of the anticipated    product.    Efficacy Models

Antibacterial activity can be determined by several standard methodswell known by those skilled in the art, including disc diffusionsmethods, broth dilution minimal inhibitory concentration (MIC) methods,etc., including the detailed method outlined below.

Anti-fungal activity can be determined by several standard methods wellknown by those skilled in the art (see for instance, U.S. Pat. No.5,885,782), including disc diffusion methods, broth dilution minimalinhibitory concentration (MIC) methods and microplate growth assay.

Antiviral activity can be determined by several standard methods wellknown by those skilled in the art including plaque-forming ability orcytopathic effects on cells in tissue culture or the ability to preventor ameliorate symptoms of viral infection in in vivo.

MIC, Broth Dilution Method

Cultures of bacteria are initially brought up from the freezer bystreaking a loopful onto agar plates under the appropriate conditions.For instance stocks are streaked onto chocolate agar and then incubatedfor 18 hours at 35-37° C. in a 5% CO₂ incubator. Five to 10 colonies arepicked from the chocolate agar plate for subculture to Brain-HeartInfusion (BHI) broth or Mueller Hinton broth or BHI containing 4% serumand incubated under the appropriate conditions. The ability of the testcompound to act as an antimicrobial is determined by the ability toinhibit bacterial, algae, or fungal growth in vitro. The optical densityof the culture of organisms in the presence of an active compound iscompared to the optical density of the same organism untreated. Theactivity of the compounds is described as either negative or the lowestconcentration inhibiting growth.

The results shown in Table 1 and Table 2 demonstrate that compounds ofthe invention have anti-infective activity. TABLE 1 AntibacterialActivity Data Antibacterial Activity against S. aureus Example # MIC(μg/mL) 1 1 2 1 3 8 4 2 5 1 6 4 7 1 8 0.5 9 1 10 3 11 12.5 12 1.6 13 3.114 0.8 15 0.4 16 0.8 17 6.2 18 3.1 19 6.2 20 1.6 21 3.1 22 1.6 23 1.6 241.6 25 0.8 26 0.8 27 0.8 28 6.2 29 0.8 30 0.8 31 1.6 32 1.6 33 1.6 343.1

TABLE 2 Antibacterial activity MIC Anti-Bacterial Activity (μg/ml)Bacteria Ex 1 Ex 2 Ex 3 Ex 4 Ex 5 Ex 6 Ex 7 Ex 8 Ex 9 S. epidermidis 2 16 2 1 3 1 1 2 S. pneumoniae 6 6 6 3 3 6 3 3 6 S. pyogenes 6 6 13 13 1313 6 13 6 E. faecalis 3 2 13 3 2 3 2 1 2 C. diphtheriae 2 1 6 2 1 3 2 12 M. smegimatis 3 2 6 2 1 3 1 1 2 M. catarrhalis 2 1 3 1 1 3 1 1 2 H.influenzae 1 1 13 6 3 13 6 3 6 H. pylori ND 16 ND ND ND ND ND 31 16ND = Not determined

TABLE 3 Antibacterial activity of 2,2Bis(4-hydroxy-3-methylphenyl)heptane in wound healing model. Efficacy in WoundVEHICLE Healing Model PEG 200 + PEG600 + PEG200/Ascorbate +Ethanol/Propylene Glycol + Beta Cyclo Dextran − Sodium laurylsulfate/Propylene − glycol/stearylalcoholPT-Transcutol/Precirol/Petrolatum −2,2Bis(4-hydroxy-3-methylphenyl)heptane was formulated in the vehiclesindicated and the activity in the wound healing model as described belowwas determined. Efficacy was evaluated by determining the reduction inbacterial load in the wound.Helicobacter pylori Colonization Model

The Helicobacter gastric colonization model, using methods generallyknown to those skilled in the art, is employed to evaluate theantibiotic activity against H. pylori or H. felis in vivo. For example,groups of female Balb/C mice (˜6 weeks of age) are colonized, thentreated with test compound (for example, one week later). Following aperiod of time, half of the stomach from mice are scraped and platedonto bacterial culture medium, for instance BHI agar containingantibiotics and horse serum. The plates are incubated and coloniescounted to determine whether any bacteria is recovered in thegastrointestinal tract after treatment. Additionally, urease enzymaticassay, using methods generally known to those skilled in the art, isused to determine whether urease activity from Helicobacter is present.The absence of or reduction of bacteria on the culture plate or ureaseactivity from treated mice, compared to that from non-treated mice,indicates the test substance is effective as an antibiotic against H.pylori or H. felis.

Sepsis Model

The sepsis model, using methods generally known by those skilled in theart, is used to evaluate the prophylactic antibiotic efficacy of testcompounds against a number of bacteria. Basic methods include, forexample, challenging mice intraperitoneally with a lethal amount of oneor more bacteria, for example Staphylococcus aureus, and 7% mucin.Approximately 1 hr before or after challenge, the mice are treated byany route of administration, for example, subcutaneously, orally orintraperitoneally, with various concentrations of test compound.Vancomycin or another antibiotic is administered to a group of mice asthe positive control and the placebo group of mice is administered thevehicle alone. Mortality is monitored for 96 hr. A reduction of thecomparative mortalities or an increase in survival time in the variousexperimental groups provides evidence of efficacy of the test compound.

Wound Healing Model

The wound healing model, using methods generally known by those skilledin the art, is used to measure the efficacy of topically appliedcompounds in suitable vehicles against any bacteria, for example,Staphylococcus epidermis, Staphylococcus aureus, Streptococcuspyrogenes, Haemophilus influenzae, or mixtures thereof. By removingseveral epidermal layers by surgical procedure, a superficial wound ofapproximately 1 cm² was created. About 10⁵cfu/20 ul of culture medium ofany bacteria, for example, S aureus, was applied to the wound. The woundwas occluded with a sterile plastic film and secured with an adhesivetap After 24 hours, topical therapy with the test compound, placeboointment, a suitable positive control ointment (i.e.neomycin-polymyxin-B-bacitracin topical ointment or triclosan ointment)(twice daily) was initiated. At the appropriate time, for instance 72hours post-infection, the wound was sampled for microbial burden. Areduction in bacterial load in the wound is evidence that the compoundis efficacious.

Alternatively, the backs of mice or rabbits are shaved. Gently scrapingthe skin, a superficial wound is created. About 10⁴ cfu/20 ul of anybacteria, for example, S aureus, is applied to the wound. The latter isoccluded with a sterile plastic film and secured with an adhesive tape.Topical therapy is employed using the above-mentioned treatment regimen.The wound is swabbed to determine the microbial load. The swab wasimmersed in a defined volume of diluent and dilutions were made andplated on appropriate nutritive agar plates. A reduction is bacterialload in the wound is evidence that the compound is efficacious.

As shown in FIGS. 1-3 a composition comprising the compound of Example 9was efficacious in reducing the population levels of pathogenic bacteriasuch as methicillin-susceptible and methicillin resistant Staphylococcusaureus and Staphylococcus epidermidis.

Shigella Wasting Model

Using methods well known to those skilled in the art, the Shigellasublethal wasting model is used to evaluate the antibiotic activityagainst Shigella flexneri or Shigella sonnei. For example, groups ofmice are challenged intranasally with a sublethal wasting dose (˜10⁵cfu) of either live Shigella flexneri or Shigella sonnei. Immediatelybefore and at 1, 2, 5 and 7 days following challenge animals are weighedand the mean group weight determined. Approximately 1 hour afterchallenge, the mice are treated by any route of administration, forexample, subcutaneously, orally or intravenously, with variousconcentrations of test compound. A suitable antibiotic is administeredto a group of mice as the positive control and the placebo group of miceis administered vehicle alone. Antibiotic activity is measured by areduction of weight loss.

Campylobacter jejuni Lethality Model

Using methods well known to those skilled in the art, the C. jejunimortality model is used to evaluate the antibiotic activity againstCampylobacter jejuni. For example, groups of mice are challenged with asingle lethal dose of live C. jejuni (˜10⁸ cfu) mixed with iron dextranin endotoxin free PBS delivered intraperitoneally. Approximately 1 hourafter challenge, the animals are treated by any route of administration,for example, subcutaneously, orally or intraperitoneally, with variousconcentrations of test compound. A suitable antibiotic is administeredto a group of animals as the positive control and the placebo group ofanimals is administered vehicle alone. Antibiotic activity is measuredby a reduction in mortality.

Campylobacter jejuni Fecal Shedding Model

Using methods well known to those skilled in the art, the C. jejunifecal shedding model is used to evaluate the antibiotic activity againstCampylobacter jejuni. For example, BALB/c mice are challenged nasally ororally with 10⁸ C. jejuni. Approximately 1 hour after challenge, themice are treated by any route of administration, for example,subcutaneously, orally or intraperitoneally, with various concentrationsof test compound. A suitable antibiotic is administered to a group ofmice as the positive control and the placebo group of mice isadministered vehicle alone. The duration of fecal shedding is determinedby monitoring over a 9 day period. Antibiotic activity is measured by areduction in numbers of bacteria shed.

Chlamydia pneumoniae Lung Model

Using methods well known to those skilled in the art, the Chlamydiapneumoniae lung model is used to evaluate the antibiotic activityagainst Chlamydia pneumoniae. For example, BALB/c are inoculatedintranasally with approximately 5×10⁵ IFU of C. pneumoniae, strain AR39in 100 μl of SPG buffer. Approximately 1 hour after challenge, the miceare treated by any route of administration, for example, subcutaneously,orally or intravenously, with various concentrations of test compound. Asuitable antibiotic is administered to a group of mice as the positivecontrol and the placebo group of mice is administered vehicle alone.

Lungs are taken from mice at days 5 and 9 post-challenge and immediatelyhomogenized in SPG buffer (7.5% sucrose, 5 mM glutamate, 12.5 mMphosphate pH 7.5). The homogenate is stored frozen at −70° C. untilassay. Dilutions of the homogenate are assayed for the presence ofinfectious Chlamydia by inoculation onto monolayers of susceptible cells(for example HL cells). The inoculum is centrifuged onto the cells andthe cells are incubated for three days at 35° C. in the presence of 1μg/ml cycloheximide. After incubation the monolayers are fixed withformalin and methanol then immunoperoxidase stained for the presence ofChlamydial inclusions using convalescent sera from rabbits infected withC. pneumoniae and metal-enhanced DAB as a peroxidase substrate.Antibiotic activity is measured by a reduction in numbers of Chlamydia.

Chlamydia trachomatis Infertility Model

Using methods well known to those skilled in the art, the Chlamydiatrachomatis infertility model is used to evaluate the antibioticactivity against Chlamydia trachomatis. Female C3HeOuJ mice areadministered a single intraperitoneal dose of progesterone (2.5 mg inpyrogen-free PBS, Depo-Provera, Upjohn) to stabilize the uterineepithelium. One week later, animals are infected by bilateralintraoviduct inoculation with approximately 5×10⁵ inclusion formingunits (IFU) of C. trachomatis (including but not limited to serovar F,strain NI1) in 100 μl of sucrose phosphate glutamate buffer (SPG). Atthe appropriate time (for example, approximately 1 hour or 1 week afterchallenge), the mice are treated by any route of administration, forexample, subcutaneously, orally or intravenously, with variousconcentrations of test compound. A suitable antibiotic is administeredto a group of mice as the positive control and the placebo group of miceis administered vehicle alone. At week 3, females from each group arecaged with 8-10 week old male C3H mice for a 2 month breeding period toassess fertility (1 male for every 2 females per cage with weeklyrotation of the males within each group, animals from differentexperimental groups were not mixed). Palpation and periodic weighing areused to determine when animals in each pair become pregnant. Theparameters used to estimate group fertility are: F, the number of micewhich littered at least once during the mating period divided by thetotal number of mice in that study group; M, the number of newborn mice(born dead or alive) divided by the number of litters produced in thatgroup during the mating period; and N, the number of newborn mice (borndead or alive) divided by the total number of mice in that group.Antibiotic activity is measured by an increase in fertility.

Chlamydia Vaginal Infection Model

Using methods well known to those skilled in the art, the Chlamydiatrachomatis vaginal infection model is used to evaluate the antibioticactivity against Chlamydia trachomatis. For example, groups of mice arevaginally challenged with a dose of live C. trachomatis in endotoxinfree PBS. Approximately 1 hour after challenge, the animals are treatedby any route of administration, for example, subcutaneously, orally,intravaginally or intraperitoneally, with various concentrations of testcompound. A suitable antibiotic is administered to a group of animals asthe positive control and the placebo group of animals is administeredvehicle alone. Vaginal clearance rates are determined for each group bysampling (swab) and cultivation of vaginal secretions. Antibioticactivity is measured by a reduction in the number of bacteria.

Neisseria gonorrhoeae Lethality Model

Using methods well known to those skilled in the art, the N. gonorrhoeaemortality model is used to evaluate the antibiotic activity againstNeisseria gonorrhoeae. For example, groups of mice are challenged with asingle lethal dose of live N. gonorrhoeae (˜10⁸ cfu) and 7% mucin inendotoxin free PBS delivered intraperitoneally. Approximately 1 hourafter challenge, the animals are treated by any route of administration,for example, subcutaneously, orally or intraperitoneally, with variousconcentrations of test compound. A suitable antibiotic is administeredto a group of animals as the positive control and the placebo group ofanimals is administered vehicle alone. Antibiotic activity is measuredby a reduction in mortality.

Neisseria gonorrhoeae Vaginal Challenge Model

Using methods well known to those skilled in the art, the N. gonorrhoeaevaginal infection model is used to evaluate the antibiotic activityagainst Neisseria gonorrhoeae. For example, groups of mice are vaginallychallenged with a dose of live N. gonorrhoeae in endotoxin free PBS.Approximately 1 hour after challenge, the animals are treated by anyroute of administration, for example, subcutaneously, orally orintraperitoneally, with various concentrations of test compound. Asuitable antibiotic is administered to a group of animals as thepositive control and the placebo group of animals is administeredvehicle alone. Vaginal clearance rates are determined for each group bysampling (swab) and cultivation of vaginal secretions. Antibioticactivity is measured by a reduction in the number of N. gonorrhoeae.

Giardia Model

Compounds are tested for in vitro growth inhibitory activity againstGiardia lamblia using methods described in Katiyar, S. K. and Edind, T.D., Antimicroorganisms and Chemotherapy, vol. 35, pp. 2198-2202 (1991)which is incorporated herein in its entirety. EC50 values for testcompounds, expressed in parts per million (ppm), were calculated fromdose response curves. As used herein, the terminology “EC50” means theconcentration of test compound required to inhibit growth by 50% arecompared to a control lacking the test compound A suitable antibiotic,for instance, Metronidazole is included as a standard in the tests forcomparative purposes.

Ophthalmic Infection Model

Anesthetized animals are inoculated with the appropriate number ofStaphylococcus aureus or Pseudomonas aeruginosa colony forming units.After approximately 24 hours, animals are treated by any means, forinstance topically, orally, intravenously, or intraperitoneally, withformulations of various concentrations of test antibiotics at variousfrequencies for 1 to 2 days. Corneas are excised from euthanized animalsand are homogenized. The homogenate is plated onto bacterial culturemedium, for instance trypticase soy agar plates. The plates areincubated and colonies counted to determine whether any bacterium arerecovered. The absence of or reduction of bacteria on the culture platetreated animals, compared to that from non-treated animals, indicatesthe test substance is effective as an antibiotic against the testorganism.

Candida albicans Skin Infection Model

Three days before infection, suitable numbers of mice are treated i.p.with cyclophosphamide (approximately 150 mg/kg). On Day 0, the backs ofmice are shaved. Gently scraping the skin, a superficial wound iscreated. About 10 6 cfu of Candida albicans in approximately 0.1 ml isapplied to the wound. The wound is occluded with a sterile plastic filmand secured with an adhesive tape. Beginning approximately 30 hoursafter the yeast challenge, the test material is applied topically once aday, twice a day or three times a day for five consecutive days. Anappropriate anti-fungal (i.e. clotrimazole) is administered a variousfrequencies, for instance twice a day, to one group of mice as apositive control. Two days after the last treatment, the mice aresacrificed and the treated area excised and homogenized in sterilesaline. The homogenate is diluted and plated on appropriate agar plates(i.e. Sabauroud's agar plates+selective antibiotics and incubated at theappropriate temperature A reduction is bacterial load in the wound isevidence that the compound is efficacious.

Trichomonas Model

Representative tests of the activity of test compound againstTrichomonas vaginalis is carried out by the two-fold tube dilutionmethod. Trichomonas vaginalis is grown on Trichomonas Culture MediumBase (Merck) plus 10% horse serum approximately 10⁵ organisms/ml andincubated under the appropriate conditions. The ability of the testcompound to act as an antimicrobial is determined by the ability toinhibit growth of Trichomonas vaginalis.

Diabetic Wound Model

Rats or mice are rendered diabetic by an injection of streptozotocin.Approximately 6 weeks after injection of streptozotocin, excisionalwounds are made on the abdomen or thighs. Animals are anesthetized andhair from the wound area removed. Wound areas are marked using atemplate and the area of skin is removed to the depth of the musclefascia using dissecting scissors and forceps. The wounds are treatedwith test compound or appropriate positive control antibiotic at variousfrequencies. Wound area is measured at various days. A reduction in thewound area in treated versus non-treated controls is evidence ofefficacy.

While the preferred embodiments of the invention have been illustratedand described, it will be appreciated that various changes can be madetherein without departing from the spirit and scope of the invention.

1. An antimicrobial composition comprising a compound of the followingformula I,

wherein a may be absent or is a single C—C bond; X¹ and X² may be at anyposition on benzene ring and are independently hydrogen, a C1-C20 alkylgroup or a C2-C20 alkenyl group which may be branched or unbranched or aC3-C20 hydrocarbon group which may be substituted or unsubstitutedcycloalkyl group, chloro, bromo, fluoro, methoxy, ethoxy, dimethylamino,dimethylaminomethyl; Y¹ and Y² may be at any position on benzene ringand are independently hydrogen, chloro, bromo, fluoro, cyano and nitrogroup; R¹ and R² are independently hydrogen, a C1-C20 alkyl group whichmay be branched or unbranched or a C3-C20 hydrocarbon group which may besubstituted or unsubstituted cycloalkyl group or R¹ and R² are such thattogether they may form a C5-C20 substituted or unsubstituted hydrocarbonring; R⁷ and R^(7′) are independently one of the following: hydrogen or

wherein R⁹ is H, substituted or unsubstituted straight chain, branchedor cyclic alkyl, alkenyl or alkynyl, —Ar or —(C₂)_(n)Ar,—(C₂)_(m)C(═O)R¹¹, —(C₂)_(n)CN, heterocyclyl, heteroaryl,—(C₂)_(n)-heterocycyl, —(C₂)_(n)-heteroaryl, m=1, 2, 3, 4, 5, 6 n=1, 2,3, 4, 5, 6, R¹¹ is H, a substituted or unsubstituted straight chain,branched or cyclic lower alkyl, lower alkenyl or lower alkynyl, or an—Ar or —(C₂)_(n)Ar; R⁸ is independently hydrogen, a cephalosporin moietyincluding but not limited to one of the following:

where R¹⁰ includes but is not limited to benzylsulfanylmethyl,phenoxymethyl, hydroxy-phenylmethyl, (thiophen-2-yl)methyl, or(2-amino-thiazol-4-yl)methoxyimino-methyl moiety or R⁸ is a penem moietyincluding but not limited to one of the following:

wherein the hydroxy group, OR⁸, R⁷ and R^(7′) may be at any position onthe benzene ring and an acceptable carrier.
 2. A compound of Formula II,

wherein X¹ and X² may be at any position on benzene ring and areindependently hydrogen, a C1-C20 alkyl group or a C2-C20 alkenyl groupwhich may be branched or unbranched or a C3-C20 hydrocarbon group whichmay be substituted or unsubstituted cycloalkyl group, chloro, bromo,fluoro, methoxy, ethoxy, dimethylamino, dimethylaminomethyl; Y¹ and Y²may be at any position on benzene ring and are independently hydrogen,chloro, bromo, fluoro, cyano and nitro group; R³, R^(3′), and R⁴ areindependently hydrogen, chloro, bromo, fluoro, cyano, trifluoromethyl, aC1-C20 alkyl group which may be branched or unbranched or a C3-C20hydrocarbon group which may be substituted or unsubstituted cycloalkylgroup, R³ and R⁴ are such that together they may form a C4-C15substituted or unsubstituted hydrocarbon ring or R^(3′) and R³ are suchthat together they may form a C3-C15 substituted or unsubstitutedhydrocarbon ring; R⁷ and R^(7′) are independently one of the following:hydrogen or

wherein R⁹ is H, substituted or unsubstituted straight chain, branchedor cyclic alkyl, alkenyl or alkynyl, —Ar or —(C₂)_(n)Ar,—(C₂)_(m)C(═O)R¹¹, —(C₂)_(n)CN, heterocyclyl, heteroaryl,—(C₂)_(n)-heterocycyl, —(C₂)_(n)-heteroaryl, m=1, 2, 3, 4, 5, 6; n=1, 2,3, 4, 5, 6, R¹¹ is H, a substituted or unsubstituted straight chain,branched or cyclic lower alkyl, lower alkenyl or lower alkynyl, or an—Ar or —(C₂)_(n)Ar; R⁸ is independently hydrogen, a cephalosporin moietyincluding but not limited to one of the following:

Where R¹⁰ includes but is not limited to benzylsulfanylmethyl,phenoxymethyl, hydroxyphenylmethyl, (thiophen-2-yl)methyl, or(2-aminothiazol-4-yl)-methoxyimino-methyl groups or R⁸ is a penemmoiety, including but not limited to one of the following:

wherein the hydroxy group, OR⁸, R⁷ and R^(7′) may be at any position onthe benzene ring.
 3. A compound of the following formula III,

wherein X¹ and X² may be at any position on benzene ring and areindependently hydrogen, a C1-C20 alkyl group or a C2-C20 alkenyl groupwhich may be branched or unbranched or a C3-C20 hydrocarbon group whichmay be substituted or unsubstituted cycloalkyl group, chloro, bromo,fluoro, methoxy, ethoxy, dimethylamino, dimethylaminomethyl; Y¹ and Y²may be at any position on benzene ring and are independently hydrogen,chloro, bromo, fluoro, cyano and nitro group; R⁵, R⁵′, and R⁶ areindependently hydrogen, chloro, bromo, fluoro, cyano, trifluoromethyl, aC1-C20 alkyl group which may be branched or unbranched or a C3-C20hydrocarbon group which may be substituted or unsubstituted cycloalkylgroup, R⁵ and R⁶ are such that together they may form a C5-C15substituted or unsubstituted hydrocarbon ring, or R⁵′ and R⁵ are suchthat together they may form a C3-C15 substituted or unsubstitutedhydrocarbon ring; R⁷ and R^(7′) are independently one of the following:hydrogen or

wherein R⁹ is H, substituted or unsubstituted straight chain, branchedor cyclic alkyl, alkenyl or alkynyl, —Ar or (C₂)_(n)Ar,—(C₂)_(m)C(═O)R¹¹ , —(C₂)_(n)CN, heterocyclyl, heteroaryl,—(C₂)_(n)-heterocycyl, —(C₂)_(n)-heteroaryl, m=1, 2, 3, 4, 5, 6; n=1, 2,3, 4, 5, 6, R¹¹ is H, a substituted or unsubstituted straight chain,branched or cyclic lower alkyl, lower alkenyl or lower alkynyl, or an—Ar or —(C₂)_(n)Ar; R⁸ is independently hydrogen, a cephalosporin moietyincluding but not limited to one of the following:

where R¹⁰ includes but is not limited to benzylsulfanylmethyl,phenoxymethyl, hydroxyphenylmethyl, (thiophen-2-yl)methyl, or(2-aminothiazol-4-yl)-methoxyimino-methyl moiety or R8 is a penem moietyincluding but not limited to one of the following:

wherein the hydroxy group, OR₈, R⁷ and R^(7′) may be at any position onthe benzene ring.
 4. An antimicrobial composition comprising a compoundthe following Formula

wherein X¹ and X² are independently hydrogen, methyl, ethyl, isopropyl,cyclopropyl, or chloro group; Y¹ and Y² are independently hydrogen,chloro, bromo, fluoro, cyano or nitro group; R¹, R² are independentlyhydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl or octyl,or R¹ and R² when taken together with the carbons to which they areattached represent cyclic hydrocarbons selected from the groupconsisting of cyclopentylidene, cycloheptylidene, cyclooctylidene or4-substituted-cyclohexylidene wherein the substituents are selected fromthe group consisting of hydrogen, methyl, ethyl, isopropyl andtert-butyl group; and an acceptable carrier.
 5. A compound of thefollowing formula

wherein X¹ and X² are independently hydrogen, methyl, ethyl, isopropyl,cyclopropyl or chloro group; Y¹ and Y² are independently hydrogen,chloro, bromo, fluoro, cyano or nitro group; and R³ is hydrogen, methyl,ethyl, n-propyl, n-butyl, tert-butyl, 2-methylpropyl, cyclopropyl,cyclobutyl, spirocyclopropyl and spirocyclobutyl group.
 6. A compound ofthe following formula

wherein X¹ and X² are independently hydrogen, methyl, ethyl, isopropylor chloro group; Y¹ and Y² are independently hydrogen, chloro, bromo,fluoro, cyano or nitro group; R⁴ is hydrogen, methyl, ethyl, n-propyl,n-butyl, tert-butyl, 2-dimethylpropyl, cyclopropyl, cyclobutyl,spirocyclopropyl and spirocyclobutyl group; and Z is hydrogen, bromo,chloro, fluoro, methyl, ethyl, or cyano.
 7. The composition of claim 1,wherein the composition further includes one or more therapeutic agentsselected from the group consisting of antibiotics, steroids, vaccines,anti-oxidants, zinc chloride, ascorbic acid, ascorbate, dextran sulfate,non-steroidal anti-inflammatories, antacids, antibodies, chelators,interferons, proteases, glucosidases, pectinases, amylases, lipasesand/or cytokines.
 8. The composition of claim 1, wherein the compositionfurther includes one or more agents selected from the group consistingof boric acid, polyvinyl pyrrolidone, benzoyl peroxide, ascorbate, EDTA,polymixin B, propylene glycol, isopropanol, PEG 600, PEG 200, and PEG8000.
 9. A composition comprising the compound of claim 2 and apharmaceutically acceptable carrier.
 10. The composition of claim 9,wherein the composition further includes one or more therapeutic agentsselected from the group consisting of antibiotics, steroids, vaccines,anti-oxidants, zinc chloride, ascorbic acid, ascorbate, dextran sulfate,non-steroidal anti-inflammatories, antacids, antibodies, chelators,interferons, proteases, glucosidases, pectinases, amylases, lipasesand/or cytokines.
 11. The composition of claim 9, wherein thecomposition further includes one or more agents selected from the groupconsisting of boric acid, polyvinyl pyrrolidone, benzoyl peroxide,ascorbate, EDTA, polymixin B, propylene glycol, isopropanol, PEG 600,PEG 200, and PEG
 8000. 12. A composition comprising the compound ofclaims 3 and a pharmaceutically acceptable carrier.
 13. The compositionof claim 12, wherein the composition further includes one or moretherapeutic agents selected from the group consisting of antibiotics,steroids, vaccines, anti-oxidants, zinc chloride, ascorbic acid,ascorbate, dextran sulfate, non-steroidal anti-inflammatories, antacids,antibodies, chelators, interferons, proteases, glucosidases, pectinases,amylases, lipases and/or cytokines.
 14. The composition of claim 12,wherein the composition further includes one or more agents selectedfrom the group consisting of boric acid, polyvinyl pyrrolidone, benzoylperoxide, ascorbate, EDTA, polymixin B, propylene glycol, isopropanol,PEG 600, PEG 200, and PEG
 8000. 15. A method of treating objects byremoving, destroying, or inhibiting the growth or activity ofmicroorganisms on inanimate objects, or on or within living animals orplants by administering an effective amount of a composition comprisinga compound according to claim 1 and a carrier.
 16. A method of treatingobjects by removing, destroying, or inhibiting the growth or activity ofmicroorganisms on inanimate objects, or on or within living animals orplants by administering an effective amount of a composition comprisinga compound according to claim 2 and a carrier, in an effective amount toa living animal or plant, or inanimate object requiring such treatment,17. A method of treating objects by removing, destroying, or inhibitingthe growth or activity of microorganisms on inanimate objects, or on orwithin living animals or plants by administering an effective amount ofa composition comprising a compound according to claim 3 and a carrier.18. A composition comprising the compound of claim 4 and apharmaceutically acceptable carrier.
 19. The composition of claim 18,wherein the composition further includes one or more therapeutic agentsselected from the group consisting of antibiotics, steroids, vaccines,anti-oxidants, zinc chloride, ascorbic acid, ascorbate, dextran sulfate,non-steroidal anti-inflammatories, antacids, antibodies, chelators,interferons, proteases, glucosidases, pectinases, amylases, lipasesand/or cytokines.
 20. The composition of claim 18 wherein thecomposition further includes one or more agents selected from the groupconsisting of boric acid, polyvinyl pyrrolidone, benzoyl peroxide,ascorbate, EDTA, polymixin B, propylene glycol, isopropanol, PEG 600,PEG 200 and PEG
 8000. 21. A composition comprising the compound of claim5 and an pharmaceutically acceptable carrier.
 22. The composition ofclaim 21, wherein the composition further includes one or moretherapeutic agents selected from the group consisting of antibiotics,steroids, vaccines, anti-oxidants, zinc chloride, ascorbic acid,ascorbate, dextran sulfate, non-steroidal anti-inflammatories, antacids,antibodies, chelators, interferons, proteases, glucosidases, pectinases,amylases, lipases and/or cytokines.
 23. The composition of claim 21,wherein the composition further includes one or more agents selectedfrom the group consisting of boric acid, polyvinyl pyrrolidone, benzoylperoxide, ascorbate, EDTA, polymixin B, propylene glycol, isopropanol,PEG 600, PEG 200, and PEG
 6000. 24. A composition comprising thecompound of claim 6 and an pharmaceutically acceptable carrier.
 25. Thecomposition of claim 24, wherein the composition further includes one ormore therapeutic agents selected from the group consisting ofantibiotics, steroids, vaccines, anti-oxidants, zinc chloride, ascorbicacid, ascorbate, dextran sulfate, non-steroidal anti-inflammatories,antacids, antibodies, chelators, interferons, proteases, glucosidases,pectinases, amylases, lipases and/or cytokines.
 26. The composition ofclaim 24, wherein the composition further includes one or more agentsselected from the group consisting of boric acid, polyvinyl pyrrolidone,benzoyl peroxide, ascorbate, EDTA, polymixin B, propylene glycol,isopropanol, PEG 600, PEG 200, and PEG
 8000. 27. A method of treatingobjects by removing, destroying, or inhibiting the growth or activity ofmicroorganisms on inanimate objects, or on or within living animals orplants by administering an effective amount of a composition comprisinga compound of claim 4 and a carrier.
 28. A method of treating objects byremoving, destroying, or inhibiting the growth or activity ofmicroorganisms on inanimate objects, or on or within living animals orplants by administering an effective amount of a composition comprisingthe compound of claim 5 and a carrier.
 29. A method of treating objectsby removing, destroying, or inhibiting the growth or activity ofmicroorganisms on inanimate objects, or on or within living animals orplants by administering an effective amount of a composition comprisinga compound of claim 6 and a carrier.
 30. A compound having the followingFormula

wherein X¹ and X² are independently hydrogen, methyl, ethyl, isopropyl,cyclopropyl or chloro group; Y¹ and Y² are independently hydrogen,chloro, bromo, fluoro, cyano or nitro group; R¹, R² are independentlyhydrogen, C1-10 alkyl group which may be branched or unbranched, orC3-C10 hydrocarbon group which may be a substituted or unsubstitutedcycloalkyl group; R¹ and R² when taken together with the carbons towhich are attached a C5-C10 cyclic hydrocarbon with substituentsselected from the group consisting of hydrogen, methyl, ethyl, isopropyland tert-butyl group at any positions on the ring.
 31. A compound of thefollowing formula

wherein X¹ and X² are independently hydrogen, methyl, ethyl, isopropyl,cyclopropyl or chloro group; Y¹ and Y² are independently hydrogen,chloro, bromo, fluoro, cyano group; R³, R³′ and R⁴ are independentlyhydrogen, C1-C10 alkyl group which may be branched or unbranched, orC3-C10 hydrocarbon group which may be substituted or unsubstitutedcycloalkyl group, or R³ and R³′ when taken together with the carbons towhich they are attached represent C3-C10 cyclic hydrocarbons withsubstituents selected from the group consisting of hydrogen, methyl,ethyl, isopropyl, tert-butyl and neopentyl group at any positions on thering.
 32. A compound of the following formula

wherein X¹ and X² are independently hydrogen, methyl, ethyl, isopropyl,cyclopropyl or chloro group; Y¹ and Y² are independently hydrogen,chloro, bromo, fluoro, cyano group; R⁵, R⁵′ and R⁶ are independentlyhydrogen, C1-C10 alkyl group which may be branched or unbranched, orC3-C10 hydrocarbon group which may be substituted or unsubstitutedcycloalkyl group, or R⁵ and R⁵′ when taken together with the carbons towhich they are attached represent C3-C10 cyclic hydrocarbons withsubstituents selected from the group consisting of hydrogen, methyl,ethyl, isopropyl and tert-butyl group at any positions on the ring. 33.A composition comprising the compound of claim 30 and a pharmaceuticallyacceptable carrier.
 34. The composition of claim 33, wherein thecomposition further includes one or more therapeutic agents selectedfrom the group consisting of antibiotics, steroids, vaccines,anti-oxidants, zinc chloride, ascorbic acid, ascorbate, dextran sulfate,non-steroidal anti-inflammatories, antacids, antibodies, chelators,interferons, proteases, glucosidases, pectinases, amylases, lipasesand/or cytokines.
 35. The composition of claim 33 wherein thecomposition further includes one or more agents selected from the groupconsisting of boric acid, polyvinyl pyrrolidone, benzoyl peroxide,ascorbate, EDTA, polymixin B, propylene glycol, isopropanol, PEG 600,PEG 200, and PEG
 8000. 36. A composition comprising the compound ofclaim 31 and a pharmaceutically acceptable carrier.
 37. The compositionof claim 36, wherein the composition further includes one or moretherapeutic agents selected from the group consisting of antibiotics,steroids, vaccines, anti-oxidants, zinc chloride, ascorbic acid,ascorbate, dextran sulfate, non-steroidal anti-inflammatories, antacids,antibodies, chelators, interferons, proteases, glucosidases, pectinases,amylases, lipases and/or cytokines.
 38. The composition of claim 36,wherein the composition further includes one or more agents selectedfrom the group consisting of boric acid, polyvinyl pyrrolidone, benzoylperoxide, ascorbate, EDTA, polymixin B, propylene glycol, isopropanol,PEG 600, PEG 200, and PEG
 8000. 39. A composition comprising thecompound of claim 32 and a pharmaceutically acceptable carrier.
 40. Thecomposition of claim 39, wherein the composition further includes one ormore therapeutic agents selected from the group consisting ofantibiotics, steroids, vaccines, anti-oxidants, zinc chloride, ascorbicacid, ascorbate, dextran sulfate, non-steroidal anti-inflammatories,antacids, antibodies, chelators, interferons, proteases, glucosidases,pectinases, amylases, lipases and/or cytokines.
 41. The composition ofclaim 39, wherein the composition further includes one or more agentsselected from the group consisting of boric acid, polyvinyl pyrrolidone,benzoyl peroxide, EDTA, polymixin B, propylene glycol, isopropanol, PEG600, PDG 200, and PEG
 8000. 42. A method of treating objects byremoving, destroying, or inhibiting the growth or activity ofmicroorganisms on inanimate objects, or on or within living animals orplants by administering an effective amount of a composition comprisinga compound of claim 30 and a carrier.
 43. A method of treating objectsby removing, destroying, or inhibiting the growth or activity ofmicroorganisms on inanimate objects, or on or within living animals orplants by administering an effective amount of a composition comprisinga compound of claim 31 and a carrier.
 44. A method of treating objectsby removing, destroying, or inhibiting the growth or activity ofmicroorganisms on inanimate objects, or on or within living animals orplants by administering an effective amount of a composition comprisinga compound of claim 32 and a carrier.
 45. A method of claim 15, 16, 17,27, 28, 29, 42, 43, or 44 wherein the composition is applied topically.46. A method of treating objects by removing, destroying, or inhibitingthe growth or activity of microorganisms on inanimate objects, or on orwithin living animals or plants by administering an effective amount ofa composition comprising 2,2-Bis(4-hydroxy-3-methylphenyl)heptane and acarrier.
 47. A method of claim 46 wherein the composition is appliedtopically.
 48. A method of cleaning and disinfecting an inert or livingsurface at least partly covered by a biofilm layer by contacting thebiofilm with a composition comprising one or more of the compounds ofclaims 1, 2, 3, 4, 5, 6, 30, 31 or 32 in an amount effective for eitherfully or partly removing or releasing the biofilm layer.
 49. A method ofinhibiting the formation of a biofilm on an inert or living surfacecomprising contacting a surface with a composition comprising one ormore of the compounds of the claims 1, 2, 3, 4, 5, 6, 30, 31, or
 32. 50.The method of claim 48 wherein the surface is a mucous membrane.
 51. Themethod of claim 49 wherein the surface is on a mucous membrane.
 52. Themethod of claim 48 wherein the surface is on a medical device orimplant.
 53. The method of claim 49 wherein the surface is on a medicaldevice or implant.
 54. The method of claim 48 wherein the compositionfurther comprises a protease, glucosidase, pectinase, amylase or lipase.55. The method of claim 49 wherein the composition further comprises aprotease, glucosidase, pectinase, amylase or lipase.
 56. A compound ofthe following formula

wherein X¹ and X² may be at any position on benzene ring and areindependently hydrogen, a C1-C20 alkyl group or a C2-C20 alkenyl groupwhich may be branched or unbranched or a C3-C20 hydrocarbon group whichmay be substituted or unsubstituted cycloalkyl group, chloro, bromo,fluoro, methoxy, ethoxy, dimethylamino, dimethylaminomethyl; Y¹ and Y²may be at any position on benzene ring and are independently hydrogen,chloro, bromo, fluoro, cyano and nitro group; and R¹ and R² areindependently, hydrogen, hydroxyl group, a C1-C20 alkyl group which maybe branched or unbranched or a C3-C20 hydrocarbon group which may besubstituted or unsubstituted cycloalkyl group or R¹ and R² are such thattogether they may form a C5-C20 substituted or unsubstituted hydrocarbonring
 57. A compound of the following formula

wherein R⁵ and R⁶ are independently hydrogen, chloro, bromo, fluoro,cyano, trifluoromethyl, a C1-C20 alkyl group which may be branched orunbranched or a C3-C20 hydrocarbon group which may be substituted orunsubstituted cycloalkyl group, R⁵ and R⁶ are such that together theymay form a C5-C15 substituted or unsubstituted hydrocarbon ring, orR^(5′) and R⁵ are such that together they may form a C3-C15 substitutedor unsubstituted hydrocarbon ring.